Benzylic compound

ABSTRACT

The present invention provides a protecting reagent that can be removed in a high yield even under acidic conditions and can afford a resulting product at a high purity in an organic synthesis reaction such as peptide synthesis and the like. The inventive protecting reagent is particular benzylic compound having only one hydroxyl group substituted by an organic group having an aliphatic hydrocarbon group having a carbon number of not less than 14.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority to U.S. provisional application No.61/290,371, filed on Dec. 28, 2009, and Japanese patent application No.2009-296366, filed on Dec. 25, 2009, both of which are incorporated bythis reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to a particular benzylic compound usableas a protecting reagent of a carboxyl group or a C-terminal of an aminoacid or a peptide, and the like in organic synthesis, particularlypeptide synthesis, and the like, and a method of synthesizing a peptideusing the benzylic compound.

BACKGROUND OF THE INVENTION

As a method of peptide synthesis, besides a solid phase method and aliquid phase method, a production method using a protecting group(hereinafter to be also referred to as anchor), comprising performing areaction in a homogeneous liquid phase, changing the solvent compositionafter the reaction, and isolating and purifying the reaction mixtureonly by filtration and washing has recently been proposed.

Patent document 1 and non-patent document 1 each disclose a methodcomprising using a 3,4,5-tris(n-octadecyloxy)benzyl alcohol typecompound as a protecting reagent of a carboxyl group and the like.However, an alkylation suppressive effect on removal of the protectinggroup is not described at all.

Patent documents 2-4 each disclose protecting reagents such as a3,5-di(docosyloxy)benzyl alcohol type compound, a2,4-di(docosyloxy)benzyl alcohol type compound and the like. However, analkylation suppressive effect on removal of the protecting group is notdescribed at all.

Patent document 4 also discloses a protecting reagent of a trityl type.However, the protecting group is not entirely satisfactory as an anchorsince a side reaction such as dissociation thereof even in methanol andthe like occur.

[Document List]

[patent Documents]

-   patent document 1: JP-A-2000-44493-   patent document 2: WO2006/104166-   patent document 3: WO2007/034812-   patent document 4: WO2007/122847

[Non-Patent Document]

-   non-patent document 1: Bull. Chem. Soc. Jpn., 74, 733-738 (2001)

SUMMARY OF THE INVENTION

An object of the present invention is to provide a useful benzyliccompound which enables an organic synthesis reaction to be performed ina homogeneous liquid phase, can be used as a protecting reagent (anchor)permitting isolation and purification by filtration and washing alone bychanging the solvent composition after the reaction, and affords aresulting product in a high yield and at high purity while suppressingan alkylation reaction even under acidic conditions during deprotection.

The present inventors have found that a particular benzylic compoundhaving only one hydroxyl group substituted by an organic group having analiphatic hydrocarbon group having a carbon number of not less than 14can solve the above-mentioned problem, which resulted in the completionof the present invention. The present invention is as described below.

-   [1] The present invention provides a benzylic compound represented    by the formula (I):

wherein

-   Y is a hydroxyl group or an —NHR group (R is a hydrogen atom, an    alkyl group or an aralkyl group);-   R^(a) is an organic group having an aliphatic hydrocarbon group,    which has a total carbon number of not less than 14;-   R^(b) in the number of n is each independently an alkoxy group is    having a carbon number of 1 to 6, a halogen atom, or an alkyl group    having a carbon number of 1 to 6, which is optionally substituted by    one or more halogen atoms; and n is an integer of 0-4.-   [2] The benzylic compound of [1], wherein the total carbon number of    the organic group for R^(a) is 14-200.-   [3] The benzylic compound of [1], wherein the total carbon number of    the organic group for R^(a) is 30-80.-   [4] The benzylic compound of any of [1] to [3], wherein n is an    integer of 0-2, and R^(b) in the number of n is each independently    an alkoxy group having a carbon number of 1 to 4.-   [5] The benzylic compound of any of [1] to [4], wherein R^(a) is a    group represented by the formula (a):

wherein

-   * indicates the position of a bond;-   m₁ is an integer of 1-10;-   X₁ in the number of m₁ is each independently a single bond, —O—,    —S—, —COO—, —OCONH—, —NHCO— or —CONH—;-   R₁ and R₂ in the number of ml are each independently a divalent    aliphatic hydrocarbon group having a carbon number of not less than    5; and-   R₃ is a hydrogen atom, or a group represented by the formula (I′):

wherein * indicates the position of a bond; and other symbols are asdefined in [1];

a group represented by the formula (b):

wherein

-   * indicates the position of a bond;-   m₂ is 1 or 2;-   n₁, n₂, n₃ and n₄ are each independently an integer of 0-2;-   X₂ in the number of m₂, X₂′ in the number of m₂ and X₂″ in the    number of m₂ are each independently a single bond, —O—, —S—, —COO—,    —OCONH—, —NHCO— or —CONH—;-   R₄ in the number of m₂ and R₆ in the number of m₂ are each    independently a hydrogen atom, a methyl group or an aliphatic    hydrocarbon group having a carbon number of not less than 5; and-   R₅ is an aliphatic hydrocarbon group having a carbon number of not    less than 5;

a group represented by the formula (c):

wherein

-   * indicates the position of a bond;-   m₃ is an integer of 0-15;-   n₅ is an integer of 0-11;-   n₆ is an integer of 0-5;-   X₃ in the number of m₃ is each independently a single bond, —O—,    —S—, —COO—, —OCONH—, —NHCO— or —CONH—; and-   R₇ in the number of m₃ is each independently a hydrogen atom, a    methyl group or an aliphatic hydrocarbon group having a carbon    number of not less than 5; or

a group represented by the formula (d):

wherein

-   * indicates the position of a bond;-   X₄ in the number of n₇ is a single bond, —O—, —S—, —COO—, —OCONH—,    —NHCO— or —CONH;-   R₈ is a divalent aliphatic hydrocarbon group;-   R₉ in the number of n₇ is a monovalent aliphatic hydrocarbon group;-   n₇ is an integer of 1-5; and-   Ar is an arylene group.-   [6] The benzylic compound of [5], wherein R^(a) is a group    represented by the formula (a) wherein m₁ is 1; X₁ is a single bond    or —O—; R₁ and R₂ are each independently a divalent aliphatic    hydrocarbon group having a carbon number of 5-80;-   and R₃ is a hydrogen atom, or a group represented by the formula    (I″):

wherein * indicates the position of a bond; and Y is as defined in [1],or the formula (I″′):

wherein * indicates the position of a bond; and Y is as defined in [1];

-   a group represented by the formula (b) wherein m₂ is 1; n₁, n₂, n₃    and n₄ are each independently 0 or 1; X₂, X₂′ and X₂″ are each    independently a single bond, or —O—; R₄ and R₆ are each    independently a hydrogen atom, a methyl group or an aliphatic    hydrocarbon group having a carbon number of 5 to 80; and R₅ is an    aliphatic hydrocarbon group having a carbon number of 5 to 80;-   a group represented by the formula (c) wherein m₃ is an integer of    1-5; n₅ is an integer of 0-2; n₆ is an integer of 0-3;-   X₃ in the number of m₃ is —O—; and R₇ in the number of m₃ is each    independently an aliphatic hydrocarbon group having a carbon number    of 5 to 80; or-   a group represented by the formula (d) wherein X₄ in the number of    n₇ is —O—; R₈ and R₉ in the number of n₇ are each independently a    monovalent or divalent aliphatic hydrocarbon group having a carbon    number of 5 to 80; n₇ is an integer of 1-3; and Ar is phenylene.-   [7] The benzylic compound of [5], wherein R^(a) is a group    represented by the formula (a) wherein m₁ is 1; X₁ is —O—; R₁ and R₂    are each independently an alkylene group having a carbon number of 8    to 60; and R₃ is a hydrogen atom;-   a group represented by the formula (b) wherein m₂ is 1; n₁, n₂, n₃    and n₄ are each 1; X₂, X₂′ and X₂″ are each —O—; and R₄, R₅ and R₆    are each independently an alkyl group having a carbon number of 8 to    60;-   a group represented by the formula (c) wherein m₃ is 2 or 3; n₅ is    1; n₆ is 2 or 3; X₃ in the number of m₃ is —O—; and R₇ in the number    of m₃ is each independently an alkyl group having a carbon number of    8 to 60; or-   a group represented by the formula (d) wherein X₄ in the number of    n₇ is —O—; R₈ is an alkylene group having a carbon number of 1 to 3;    R₉ in the number of n₇ is each independently an alkyl group having a    carbon number of 8 to 60; n₇ is an integer of 1-3; and Ar is    phenylene.-   [8] The benzylic compound of [5], wherein R^(a) is a group    represented by the formula (a) wherein m₁ is 1; X₁ is —O—; R₁ and R₂    are each independently an alkylene group having a carbon number of    14 to 30; and R₃ is a hydrogen atom;-   a group represented by the formula (b) wherein m₂ is 1; n₁, n₂, n3    and n4 are each 1; X₂, X₂′ and X₂″ are each —O—; and R₄, R₅ and R₆    are each independently an alkyl group having a carbon number of 14    to 30;-   a group represented by the formula (c) wherein m₃ is 2 or 3; n₅ is    1; n₆ is 3; X₃ in the number of m₃ is —O—; and R₇ in the number of    m₃ is each independently an alkyl group having a carbon number of 14    to 30; or-   a group represented by the formula (d) wherein X₄ in the number of    n₇ is —O—; R₈ is an alkylene group having a carbon number of 1 to 3;    R₉ in the number of n₇ is each independently an alkyl group having a    carbon number of 14 to 30;

n₇ is 2 or 3; and

-   Ar is phenylene.-   [9] The benzylic compound of any of [1] to [8], wherein the group    OR^(a) is present at the 2-position or the 4-position on the benzene    ring.-   [10] The benzylic compound of any of [1] to [9], wherein the group    R^(b) is a methoxy group.-   [11] The benzylic compound of any of [1] to [10], wherein Y is a    hydroxyl group.-   [12] The benzylic compound of any of [1] to [10], wherein Y is an    —NHR group wherein R is as defined in [1].-   [13] The benzylic compound of [11] or [12], which is selected from    the group consisting of 4-(12′-docosyloxy-1′-dodecyloxy)benzyl    alcohol;-   4-(12′-docosyloxy-1′-dodecyloxy)-2-methoxybenzyl alcohol;-   4-(12′-docosyloxy-1′-dodecyloxy)-2-methoxybenzylamine;-   2-(12′-docosyloxy-1′-dodecyloxy)-4-methoxybenzyl alcohol;-   2-(12′-docosyloxy-1′-dodecyloxy)-4-methoxybenzylamine;-   4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)benzyloxy]benzyl alcohol;-   2-[3′,5′-di(docosyloxy)benzyloxy]-4-methoxybenzyl alcohol;-   2-methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzyl alcohol;-   2-methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzylamine;-   4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzyl    alcohol;-   4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzyl alcohol;-   1,22-bis[12-(4-hydroxymethyl-3-methoxyphenoxy)dodecyloxy]docosane;    and-   1,22-bis[12-(2-hydroxymethyl-5-methoxyphenoxy)dodecyloxy]docosane.-   [14] The benzylic compound of [11] or [12], which is selected from    the group consisting of 2-docosyloxy-4-methoxybenzyl alcohol;-   2-methoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzyl    alcohol;-   3,5-dimethoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzyl    alcohol;-   N-(4-hydroxymethyl-3-methoxyphenyl)    3,4,5-tris(octadecyloxy)cyclohexylcarboxamide;-   N-(5-hydroxymethyl-2-methoxyphenyl)    3,4,5-tris(octadecyloxy)cyclohexylcarboxamide; and-   N-(4-hydroxymethylphenyl)    3,4,5-tris(octadecyloxy)cyclohexylcarboxamide.-   [15] A reagent for protecting a carboxyl group of amino acid or    peptide, comprising the benzylic compound of [11].-   [16] A reagent for protecting the C-terminal of amino acid or    peptide, comprising the benzylic compound of [11].-   [17] A method of producing a peptide by a liquid phase synthesis    process comprising the following steps;-   (1) a step of bonding the benzylic compound of any of [1] to [14] to    amino acid or peptide (bonding step), and-   (2) a step of precipitating a bonded product of the benzylic    compound with amino acid or peptide obtained in the above-mentioned    step (precipitation step).-   [18] A method of producing a peptide by a liquid phase synthesis    process comprising the following steps;-   (1) a step of obtaining C-protected amino acid or C-protected    peptide, comprising condensing the benzylic compound of any of [1]    to [14] with the C-terminal of N-protected amino acid or N-protected    peptide (C-terminal protection step),-   (2) a step of removing the protecting group of the N-terminal of the    amino acid or peptide obtained in the above-mentioned step    (deprotection step of N-terminal),-   (3) a step of condensing the N-terminal of the amino acid or peptide    obtained in the above-mentioned step with N-protected amino acid or    N-protected peptide (peptide chain elongation step), and-   (4) a step of precipitating the peptide obtained in the    above-mentioned step (precipitation step).-   [19] The method of [18], further comprising one or more repeats of    the following steps (5)-(7);-   (5) a step of deprotecting the N-terminal of the peptide obtained in    the precipitation step (deprotection step of N-terminal),-   (6) a step of condensing the N-terminal of peptide obtained in the    above-mentioned step with N-protected amino acid or N-protected    peptide (peptide chain elongation step), and-   (7) a step of precipitating the peptide obtained in the    above-mentioned step (precipitation step).-   [20] The method of the above-mentioned [18] or [19], further    comprising, after the precipitation step, a step of removing the    protecting group (anchor) of the C-terminal of the peptide.-   [21] A method of producing a peptide compound, comprising using the    benzylic compound of any of the above-mentioned [1] to [14].-   [22] A method of producing an organic compound, comprising using the    benzylic compound of any of the above-mentioned [1] to [14].-   [23] A benzylic compound adduct protected by the benzylic compound    of any of the above-mentioned [1] to [14].-   [24] A compound represented by the following formula (III):

wherein m₃′ is 1-3; R₇′ in the number of m₃′ is an alkylene group havinga carbon number of 14 to 30, and Z′ is a hydroxyl group or a leavinggroup.

-   [25] The compound of [24], wherein, in the formula (III), m₃′ is 3,    and Z′ is a hydroxyl group, a halogen atom, an alkylsulfonyloxy    group optionally substituted by one or more halogen atoms, or an    optionally substituted arylsulfonyloxy group.

Using the particular benzylic compound of the present invention as aprotecting reagent of a carboxyl group and the like, an organicsynthesis reaction such as peptide synthesis and the like can beperformed in a homogeneous liquid phase, and isolation and purificationcan be performed by filtration and washing alone by changing the solventcomposition after the reaction. Furthermore, a resulting product can beobtained in a high yield and at high purity while suppressing analkylation reaction even under acidic conditions during deprotection.Thus, the present invention also includes a method of producing apeptide compound, in which the improvement comprises protecting afunctional group of the peptide with the benzylic compound according toany of the embodiments described above. The present invention alsoincludes a method of producing an organic compound, where theimprovement comprises protecting a functional group with the benzyliccompound according to any of the embodiments described above.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise specified in the sentences, any technical terms andscientific terms used in the present specification, have the samemeaning as those generally understood by those of ordinary skill in theart in the art the present invention belongs to. Any methods andmaterials similar or equivalent to those described in the presentspecification can be used for practicing or testing the presentinvention, and preferable methods and materials are described in thefollowing. All publications and patents referred to in the Specificationare hereby incorporated by reference so as to describe and discloseconstructed products and methodology described in, for example,publications usable in relation to the described invention.

The present invention relates to a particular benzylic compound(hereinafter to be abbreviated as the compound of the presentinvention).

The compound of the present invention is a protecting reagent to beintroduced in organic synthesis reactions, preferably peptide synthesisand the like, as a protecting group (anchor) of a carboxyl group and thelike, that is, C-terminal of amino acid or peptide, and the like, andthe compound of the present invention suitable for the object can beappropriately selected.

The compound of the present invention is a benzylic compound representedby the following formula (I).

A benzylic compound represented by the formula (I):

wherein

-   Y is a hydroxyl group or an —NHR group (R is a hydrogen atom, an    alkyl group or an aralkyl group);-   R^(a) is an organic group having an aliphatic hydrocarbon group,    which has a total carbon number of not less than 14;-   R^(b) in the number of n is each independently a C₁₋₆ alkoxy group,    a halogen atom, or a C₁₋₆ alkyl group, which is optionally    substituted by one or more halogen atoms;-   when a plurality of R^(b) are present, respective R^(b) may be the    same or different; and-   n is an integer of 0-4.

The compound represented by the formula (I) of the present invention isbonded to a compound to be protected via group Y.

That is, the compound of the present invention wherein Y is a hydroxylgroup or an —NHR group is bonded to the C-terminal etc. of amino acid orpeptide for protection thereof.

In the present specification, examples of the “alkyl group” for Rinclude a C₁₋₃₀ alkyl group, preferably a C₁₋₁₀ alkyl group, morepreferably a C₁₋₆ alkyl group. Preferable examples include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, andthe like, and particularly preferred are methyl and ethyl.

In the present specification, examples of the “aralkyl group” for Rinclude a C₇₋₃₀ aralkyl group. Preferred is a C₇₋₂₀ aralkyl group, morepreferred is a C₇₋₁₆ aralkyl group (a C₆₋₄₀ aryl-C₁₋₆ alkyl group).Preferable examples include benzyl, 1-phenylethyl, 2-phenylethyl,1-phenylpropyl, naphthylmethyl, 1-naphthylethyl, 1-naphthylpropyl, andthe like, and particularly preferred is benzyl.

As R, a hydrogen atom, a C₁₋₆ alkyl group or a C₇₋₁₆ aralkyl group ispreferable, a hydrogen atom, methyl, ethyl or benzyl is more preferable,and a hydrogen atom is particularly preferable.

In the present specification, the “organic group having an aliphatichydrocarbon group” for R^(a) means a monovalent organic group having analiphatic hydrocarbon group in the molecular structure.

The “aliphatic hydrocarbon group” of the “organic group having analiphatic hydrocarbon group” is an aliphatic hydrocarbon groupconsisting of straight chain or branched, saturated or unsaturated, andan aliphatic hydrocarbon group having a carbon number of not less than 5is preferable, an aliphatic hydrocarbon group having a carbon number of5 to 60 is particularly preferable, an aliphatic hydrocarbon grouphaving a carbon number of 5 to 30 is more preferable, and an aliphatichydrocarbon group having a carbon number of 10 to 30 is furtherpreferable.

The site of the “aliphatic hydrocarbon group” in the organic grouphaving an aliphatic hydrocarbon group of is not particularly limited,and it may be present at the terminal (monovalent group), or other site(e.g., divalent group).

Examples of the “aliphatic hydrocarbon group” include monovalent groupssuch as an alkyl group, a cycloalkyl group, an alkenyl group, acycloalkenyl group, an alkynyl group and the like and divalent groupsderived therefrom. Preferred are monovalent groups such as a methylgroup, an ethyl group, a propyl group, an isopropyl group, a butylgroup, an isobutyl group, a sec-butyl group, a tert-butyl group, apentyl group, a hexyl group, an octyl group, a decyl group, a dodecylgroup, a lauryl group, a tridecyl group, a myristyl group, a cetylgroup, a stearyl group, an aralkyl group, a behenyl group, an oleylgroup, an isostearyl group and the like and divalent groups derivedtherefrom.

The moiety other than the “aliphatic hydrocarbon group” in the “organicgroup having an aliphatic hydrocarbon group” can be set freely. Forexample, —O—, —S—, —COO—, —OCONH— and —CONH—, and a moiety such as ahydrocarbon group (monovalent group or divalent group) and the like maybe contained as a linker. Examples of the “hydrocarbon group” include analiphatic hydrocarbon group, an aromatic aliphatic hydrocarbon group, amonocyclic saturated hydrocarbon group, an aromatic hydrocarbon groupand the like. Specifically, for example, monovalent groups such as analkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, anaryl group, an aralkyl group and the like, and divalent groups derivedtherefrom are used. As the “alkyl group”, a C₁₋₆ alkyl group and thelike are preferable and, for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like canbe mentioned. As the “alkenyl group”, a C₂₋₆ alkenyl group and the likeare preferable and, for example, vinyl, 1-propenyl, allyl, isopropenyl,butenyl, isobutenyl and the like can be mentioned. As the “alkynylgroup”, a C₂₋₆ alkynyl group and the like are preferable and, forexample, ethynyl, propargyl, 1-propynyl and the like can be mentioned.As the “cycloalkyl group”, a C₃₋₆ cycloalkyl group and the like arepreferable and, for example, cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl can be mentioned. As the “aryl group”, for example, a C₆₋₁₄aryl group and the like are preferable and, for example, phenyl,1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and the like can bementioned. Of these, a C₆₋₁₀ aryl group is more preferable, and phenylis particularly preferable. As the “aralkyl group”, a C₇₋₂₀ aralkylgroup is preferable and, for example, benzyl, 1-phenylethyl,2-phenylethyl, 1-phenylpropyl, naphthylmethyl, 1-naphthylethyl,1-naphthylpropyl and the like can be mentioned. Of these, a C₇₋₁₆aralkyl group C₆₋₁₀ aryl-O₁₋₆ alkyl group) is more preferable, andbenzyl is particularly preferable. The “hydrocarbon group” is optionallysubstituted by a substituent selected from a halogen atom (a chlorineatom, a bromine atom, a fluorine atom, an iodine atom), an alkyl grouphaving a carbon number of 1 to 6, which is optionally substituted by oneor more halogen atoms, an oxo group and the like.

The compound of the present invention has one OR^(a) group. Here, the“organic group having an aliphatic hydrocarbon group” constituting theOR^(a) group may have plural “aliphatic hydrocarbon groups” due tobranching and the like. When the “organic group having an aliphatichydrocarbon group” has plural “aliphatic hydrocarbon groups”, they maybe the same or different.

The OR^(a) group is preferably bonded to, though unlimitatively, the2-position or the 4-position on the benzene ring of the compound of thepresent invention, since the final removal of the anchor is facilitated.

In the compound of the present invention, the lower limit of the totalcarbon number of the “organic group having an aliphatic hydrocarbongroup” for R^(a) is preferably not less than 14, more preferably notless than 16, further preferably not less than 20, still more preferablynot less than 24, and particularly preferably not less than 30. In the“organic group having an aliphatic hydrocarbon group” for R^(a), theupper limit of the total carbon number is preferably not more than 200,more preferably not more than 150, further preferably not more than 120,still more preferably not more than 100, particularly preferably notmore than 80, and not more than 60 is further particularly preferable.When the carbon number is higher, crystallinity of the compound of thepresent invention in a polar organic solvent becomes fine even when thepeptide chain is a long chain.

Examples of the “organic group having an aliphatic hydrocarbon group”for R^(a) include any group selected from the following formulas (a) to(d).

A group represented by the formula (a):

in the formula (a),

-   * indicates the position of a bond;-   m₁ is an integer of 1-10;-   X₁ in the number of m₁ is each independently a single bond, —O—,    —S—, —COO—, —OCONH—, —NHCO— or —CONH—;-   R₁ and R₂ in the number of m₁ are each independently a divalent    aliphatic hydrocarbon group having a carbon number of not less than    5; and-   R₃ is a hydrogen atom, or the formula (I′):

-   wherein * indicates the position of a bond, and other symbols are as    defined above.

As the “aliphatic hydrocarbon group having a carbon number of not lessthan 5″ for R₁ or R₂, the “aliphatic hydrocarbon group” of theabove-mentioned “organic group having an aliphatic hydrocarbon group”having a carbon number of not less than 5 can be mentioned, preferablyone having a carbon number of 5 to 80.

In the formula (a), a group wherein

-   m₁ is 1;-   X₁ is a single bond, or —O—;-   R₁ and R₂ are each independently a divalent aliphatic hydrocarbon    group having a carbon number of 5 to 80; and-   R₃ is a hydrogen atom, or the formula (I″):

wherein * and Y are as defined above, or the formula (I″′):

-   wherein * and Y are as defined above, is preferable. Of these, a    group wherein-   m₁ is 1;-   X₁ is —O—;-   R₁ and R₂ are each independently an alkylene group having a carbon    number of 8 to 60; and-   R₃ is a hydrogen atom, is more preferable.

Particularly preferable group of the formula (a) is a group wherein

-   m₁ is 1;-   X₁ is —O—;-   R₁ and R₂ are each independently an alkylene group having a carbon    number of 14 to 30; and-   R₃ is a hydrogen atom.

A group represented by the formula (b):

in the formula (b),

-   * indicates the position of a bond;-   m₂ is 1 or 2;-   n₁, n₂, n₃ and n₄ are each independently an integer of 0-2;-   X₂ in the number of m₂, X₂′ in the number of m₂ and X₂″ in the    number of m₂ are each independently a single bond, —O—, —S—, —COO—,    —OCONH—, —NHCO— or —CONH—;-   R₄ in the number of m₂ and R₆ in the number of m₂ are each    independently a hydrogen atom, a methyl group or an aliphatic    hydrocarbon group having a carbon number of not less than 5; and-   R₅ is an aliphatic hydrocarbon group having a carbon number of not    less than 5.

As the “aliphatic hydrocarbon group having a carbon number of not lessthan 5″ for R₄, R₅ or R₆, the “aliphatic hydrocarbon group” having acarbon number of not less than 5, preferably 5 to 80, from the“aliphatic hydrocarbon group” of the above-mentioned “organic grouphaving an aliphatic hydrocarbon group” can be mentioned.

In the formula (b), a group wherein

-   m₂ is 1;-   n₁, n₂, n₃ and n₄ are each independently 0 or 1;-   X₂, X₂′ and X₂″ are each independently a single bond or —O—;-   R₄ and R₆ are each independently a hydrogen atom, a methyl group or    an aliphatic hydrocarbon group having a carbon number of 5-80; and-   R₅ is an aliphatic hydrocarbon group having a carbon number of 5-80    is preferable. Of these, a group wherein-   m₂ is 1;-   n₁, n₂, n₃ and n₄ are each 1;-   X₂, X₂′ and X₂″ are each —O—;-   R₄, R₅ and R₆ are each independently an alkyl group having a carbon    number of 8 to 60 is more preferable.

Particularly preferable group of the formula (b) is a group wherein

-   m₂ is 1;-   n₁, n₂, n₃ and n₄ are each 1;-   X₂, X₂′ and X₂″ are each —O—; and-   R₄, R₅ and R₆ are each independently an alkyl group having a carbon    number of 14 to 30.

A group represented by the formula (c):

wherein

-   * indicates the position of a bond;-   m₃ is an integer of 0-15;-   n₅ is an integer of 0-11;-   n₆ is an integer of 0-5;-   X₃ in the number of m₃ is each independently a single bond, —O—,    —S—, —COO—, —OCONH—, —NHCO— or —CONH—; and-   R₇ in the number of m₃ is each independently a hydrogen atom, a    methyl group or an aliphatic hydrocarbon group having a carbon    number of not less than 5.

Examples of the “aliphatic hydrocarbon group having a carbon number ofnot less than 5″ for R₇ include the “aliphatic hydrocarbon group” havinga carbon number of not less than 5, preferably 5 to 80, from the“aliphatic hydrocarbon group” of the above-mentioned “organic grouphaving an aliphatic hydrocarbon group”.

In the formula (c), a group wherein

-   m₃ is an integer of 1-5;-   n₅ is an integer of 0-2;-   n₆ is an integer of 0-3;-   X₃ in the number of m₃ is —O—; and-   R₇ in the number of m₃ is each independently an aliphatic    hydrocarbon group having a carbon number of 5-80 is preferable. Of    these, a group wherein-   m₃ is 2 or 3;-   n₅ is 1;-   n₆ is 2 or 3;-   X₃ in the number of m₃ is —O—; and-   R₇ in the number of m₃ is each independently an aliphatic    hydrocarbon group having a carbon number of 8 to 60, is more    preferable.

Particularly preferable group of the formula (c) is a group wherein

-   m₃ is 2 or 3;-   n₅ is 1;-   n₆ is 3;-   X₃ in the number of m₃ is —O—; and-   R₇ in the number of m₃ is each independently an alkyl group having a    carbon number of 14 to 30.

A group represented by the formula (d):

in the formula (d),

-   * indicates the position of a bond;-   X₄ in the number of n₇ is a single bond, —O—, —S—, —COO—, —OCONH—,    —NHCO— or —CONH—;-   R₈ is a divalent aliphatic hydrocarbon group;-   R₉ in the number of n₇ is a monovalent aliphatic hydrocarbon group;-   n₇ is an integer of 1-5; and-   Ar is an arylene group.

Examples of the “aliphatic hydrocarbon group” for R₈ or R₉ include thosesimilar to the “aliphatic hydrocarbon group” of the above-mentioned“organic group having an aliphatic hydrocarbon group”. Preferred arethose having a carbon number of not less than 5, more preferably 5 to80, particularly preferably 8 to 60.

Examples of the “arylene group” for Ar include phenylene, naphthylene,biphenylene and the like, preferably phenylene.

In the formula (d), a group wherein

-   X₄ in the number of n₇ is —O—;-   R₈ and R₉ in the number of n₇ are each independently a monovalent or    divalent aliphatic hydrocarbon group having a carbon number of 8 to    60;-   n7 is an integer of 1-3; and-   Ar is phenylene is preferable. Of these, a group wherein-   X₄ in the number of n₇ is —O—;-   R₈ is an alkylene group having a carbon number of 1 to 3;-   R₉ in the number of n₇ is each independently an alkyl group having a    carbon number of 14 to 30,-   n₇ is 2 or 3; and

Particularly preferable group of the formula (d) is a group wherein

-   X₄ in the number of n₇ is —O—;-   R₈ is a methylene group;-   R₉ in the number of n₇ is each independently an alkyl group having a    carbon number of 14 to 30,-   n₇ is 2 or 3; and-   Ar is phenylene.

Specific examples of the “organic group having an aliphatic hydrocarbongroup” include the following groups having an aliphatic carbon chain,which has a carbon number of 18 to 100. * in each group indicates theposition of a bond.

In the present specification, specific preferable examples of the “R^(b)group” include a C₁₋₆ alkoxy group (e.g., a C₁₋₄ alkoxy group such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy etc.), a C₁₋₆ alkyl group optionally substituted by one ormore halogens (e.g., a C₁₋₆ alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc., aC₁₋₆ alkyl group substituted by halogen such as trifluoromethyl,trichloromethyl etc.), or a halogen atom. Of these, a C₁₋₆ alkoxy group(particularly a methoxy group) is preferable. The benzylic compound ofthe present invention preferably does not have the “R^(b) group” on thebenzene ring, or has a C₁₋₆ alkoxy group. The “R^(b) group” is presentin the number of n in total wherein n is an integer of 0 to 4,preferably 0 to 2, more preferably 0 or 1.

Preferable examples of the benzylic compound of the present inventioninclude the following benzylic compounds.

4-(12′-docosyloxy-1′-dodecyloxy)benzyl alcohol;

-   4-(12′-docosyloxy-1′-dodecyloxy)-2-methoxybenzyl alcohol;-   4-(12′-docosyloxy-1′-dodecyloxy)-2-methoxybenzylamine;-   2-(12′-docosyloxy-1′-dodecyloxy)-4-methoxybenzyl alcohol;-   2-(12′-docosyloxy-1′-dodecyloxy)-4-methoxybenzylamine;-   2-docosyloxy-4-methoxybenzyl alcohol;-   4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)benzyloxy)benzyl alcohol;-   2-[3′,5′-di(docosyloxy)benzyloxy]-4-methoxybenzyl alcohol;-   2-methoxy-4-(2′,2′,2′-tris(octadecyloxymethyl)ethoxy)benzyl alcohol;-   2-methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzylamine;-   4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzyl    alcohol;-   2-methoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzyl    alcohol;-   4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzyl alcohol;-   3,5-dimethoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzyl    alcohol;-   N-(4-hydroxymethyl-3-methoxyphenyl)    3,4,5-tris(octadecyloxy)cyclohexylcarboxamide;-   N-(5-hydroxymethyl-2-methoxyphenyl)    3,4,5-tris(octadecyloxy)cyclohexylcarboxamide;-   N-(4-hydroxymethylphenyl)    3,4,5-tris(octadecyloxy)cyclohexylcarboxamide;-   1,22-bis[12-(4-hydroxymethyl-3-methoxyphenoxy)dodecyloxy]docosane;    and-   1,22-bis[12-(2-hydroxymethyl-5-methoxyphenoxy)dodecyloxy]docosane.

Production Method of the Compound of the Present Invention

While the production method of the compound of the present invention isnot particularly limited, it can be synthesized, for example, via thefollowing reactions.

Unless otherwise specified, the starting compound may be a commerciallyavailable product, or can be produced according to a method known per seor a method analogous thereto.

While the yield of the compound obtained by each of the followingmethods may vary depending on the reaction conditions employed, thecompound can be isolated and purified from the resulting product by ageneral method (recrystallization, column chromatography and the like),and then precipitated by a method of changing the solution temperature,a method of changing the solution composition and the like.

In each reaction, when the starting compound has a hydroxy group, anamino group, a carboxy group, a carbonyl group or the like, a protectinggroup generally used in the peptide chemistry and the like may beintroduced into these groups, and the object compound can be obtained byremoving the protecting group as necessary after the reaction.

The compound of the present invention can be produced, for example,according to the following steps.

wherein R′ is a hydrogen atom or OR″ group (wherein R″ is an alkyl groupsuch as a C₁₋₆ alkyl group and the like, an aralkyl group such as abenzyl group etc., and the like), R″′ is an alkyl group or an aralkylgroup, Z is a leaving group such as a halogen atom and the like, andother symbols are as defined above.

Step (a)

In this step, group R^(a) is introduced into a hydroxyl group of acompound represented by the formula (II) (hereinafter to be abbreviatedas compound (II)) to give a compound represented by the formula (IIa)(hereinafter to be abbreviated as compound (IIa)).

The reaction is performed in a solvent that does not influence thereaction in the presence of a base by using halide corresponding togroup R^(a) (chloride, bromide or iodide), or an alkylsulfonyloxylatedcompound corresponding to group R^(a) (e.g., a methanesulfonyloxylatedcompound etc.) or an arylsulfonyloxylated compound (e.g., ap-toluenesulfonyloxylated compound etc.), or under Mitsunobu reactionconditions of reacting compound (II) with alcohol corresponding to groupR^(a) in the presence of triphenylphosphine and diisopropylazodicarboxylate.

Examples of the base include alkali metal salt such as sodium carbonate,sodium hydrogen carbonate, potassium carbonate, sodium hydride,potassium hydride, potassium tert-butoxide and the like; organic basessuch as pyridine, triethylamine, N,N-dimethylaniline,1,8-diazabicyclo[5.4.0]undec-7-ene etc., and the like. Of these, sodiumcarbonate, potassium carbonate, sodium hydride and the like arepreferable.

Examples of the solvent include aromatic hydrocarbons such as toluene,xylene and the like; ethers such as tetrahydrofuran, dioxane and thelike; amides such as dimethylformamide, dimethylacetamide and the like;halogenated hydrocarbons such as chloroform, dichloromethane and thelike; nitriles such as acetonitrile and the like, and a mixture thereof.Of these, dimethylformamide, tetrahydrofuran, toluene,N-methylpyrrolidone and the like are preferable.

The reaction temperature is generally 50° C. to 150° C., preferably 60°C. to 130° C. The reaction time is generally 2-30 hr, preferably 3-10hr.

Step (b)

In this step, compound (IIa) is reduced to give a compound representedby the formula (I-a) (hereinafter to be abbreviated as compound (I-a)).The reduction reaction can be performed by a method using a reducingagent.

Examples of the reducing agent to be used for the reduction reactioninclude metal hydride (sodium borohydride, lithium borohydride, sodiumcyanoborohydride, sodium triacetoxyborohydride, dibutylaluminum hydride,aluminum hydride, lithium aluminum hydride, etc.) and the like. Ofthese, sodium borohydride, dibutylaluminum hydride and the like arepreferable.

The reaction is performed in a solvent that does not influence thereaction. Examples of the solvent include alcohols such as methanol,ethanol and the like; ethers such as diethyl ether, tetrahydrofuran,dioxane and the like; aromatic hydrocarbons such as toluene, xylene andthe like; and a mixture thereof. Of these, tetrahydrofuran, toluene andthe like are preferable.

The reaction temperature is generally 0° C. to 100° C., preferably 30°C. to 70° C., and the reaction time is generally 1-24 hr, preferably 2-5hr.

Step (c-1)

In this step, compound (IIa) (formula (IIa) wherein R′ is a hydrogenatom) is oximated to give a compound represented by the formula (I′-a)(hereinafter to be abbreviated as compound (I′-a)).

The oximation reaction includes reacting compound (IIa) withhydroxylamine acid addition salt in a solvent that does not influencethe reaction in the presence of a base.

Examples of the hydroxylamine acid addition salt include mineral acidsalts such as hydrochloride, sulfate, nitrate and the like, organic acidsalts such as acetate, trifluoroacetate, methanesulfonate,trifluoromethanesulfonate, p-toluenesulfonate etc., and the like, andhydrochloride is particularly preferable.

Examples of such base include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogen carbonate, potassiumcarbonate and the like; organic bases such as pyridine, triethylamine,diisopropylethylamine, N,N-dimethylaniline,1,8-diazabicyclo[5.4.0]undec-7-ene etc., and the like. Of these,triethylamine, diisopropylethylamine and the like are preferably.

Examples of the solvent include halogen solvents such as chloroform,dichloromethane and the like; aromatic hydrocarbons such as toluene,xylene and the like; ethers such as tetrahydrofuran, dioxane and thelike; and/or a mixture thereof. Of these, dichloromethane, chloroform,toluene and the like are preferable.

The reaction temperature is generally 10° C. to 100° C., preferably 20°C. to 60° C., and the reaction time is generally 0.5-30 hr, preferably2-20 hr.

Step (c-2)

In this step, compound (I′-a) is reduced by a catalytic hydrogenationreaction in the presence of a metal catalyst such as palladium-carbon,Raney-nickel and the like, or by a reducing agent such as metal hydrideand the like, which is similar to those in the aforementioned step (b),to give a compound represented by the formula (I-b) (hereinafter to beabbreviated as compound (I-b)), which is the compound of the presentinvention.

Compound (I-b) can also be produced from step (c-3) via step (c-4) andstep (c-5).

Step (c-3)

In this step, compound (I-a) is halogenated with, for example, achlorinating agent such as acetyl chloride, thionyl chloride and thelike or, for example, a brominating agent such as acetyl bromide,phosphorus tribromide, diphenylphosphine/bromine and the like to give acompound represented by the formula (I′-b) (hereinafter to beabbreviated as compound (I′-b)).

Examples of the solvent include halogenated hydrocarbons such aschloroform, dichloromethane, and the like; aromatic hydrocarbons such astoluene, xylene, and the like; ethers such as tetrahydrofuran, dioxane,and the like; and a mixture thereof. Of these, chloroform,tetrahydrofuran, toluene, and the like are preferable.

The reaction temperature is generally 10° C. to 150° C., preferably 30°C. to 80° C., and the reaction time is generally 0.5-30 hr, preferably2-20 hr.

Step (c-4)

In this step, compound (I′-b) is azidated with an azidating agent suchas sodium azide and the like to give a compound represented by theformula (I′-c) (hereinafter to be abbreviated as compound (I′-c)).

The reaction includes reacting compound (I′-b) with an azidating agentin a solvent that does not influence the reaction.

Examples of the solvent include halogenated hydrocarbons such aschloroform, dichloromethane, and the like; aromatic hydrocarbons such astoluene, xylene, and the like; ethers such as tetrahydrofuran, dioxane,and the like; amides such as N,N-dimethylformamide and the like; and amixture thereof. Of these, chloroform, N,N-dimethylformamide, and thelike are preferable.

The reaction temperature is generally 10° C. to 150° C., preferably 20°C. to 100° C., and the reaction time is generally 0.5-30 hr, preferably2-20 hr.

Step (c-5)

In this step, compound (I′-c) is aminated to give compound (I-b).

The reaction includes reacting compound (I′-c) with triphenylphosphineor catalytic hydrogenation in a solvent that does not influence thereaction in the presence of water.

The amount of triphenylphosphine to be used is preferably 1-10 mol,particularly preferably 1-5 mol, per 1 mol of compound (I′-c).

The amount of water to be used is preferably 1-10 mol, particularlypreferably 1-5 mol, per 1 mol of compound (I′-c).

Examples of the solvent include aromatic hydrocarbons such as toluene,xylene, and the like; ethers such as tetrahydrofuran, dioxane, and thelike; and a mixture thereof. Of these, toluene, tetrahydrofuran, and thelike are preferable.

The reaction temperature is generally 10° C. to 150° C., preferably 20°C. to 100° C., and the reaction time is generally 0.5-30 hr, preferably2-20 hr.

Step (c-6)

In this step, compound (I′-b) is reacted with R″′NH₂ (wherein R″′ is asdefined above) to give a compound represented by the formula (I-c)(hereinafter to be abbreviated as compound (I-c)), which is the compoundof the present invention wherein Y is an —NHR″′ group.

The reaction includes reacting compound (I′-b) with amine represented byR″′—NH₂ in a solvent that does not influence the reaction in thepresence of, where necessary, for example, a base such as tertiary amine(triethylamine, diisopropylethylamine etc.) and the like.

Examples of the solvent include aromatic hydrocarbons such as toluene,xylene, and the like; ethers such as tetrahydrofuran, dioxane, and thelike; and, halogenated hydrocarbons such as chloroform, dichloromethane,and the like and a mixture thereof. Of these, toluene, tetrahydrofuran,chloroform, and the like are preferable.

The reaction temperature is generally 10° C. to 100° C., preferably 20°C. to 60° C., and the reaction time is generally 0.5-30 hr, preferably2-20 hr.

The halide corresponding to group R^(a), which was used as a startingcompound, may be a commercially available product, or can be producedby, for example, the following steps (d-1), (d-2), (e), (f), (g), or amethod similar thereto.

Step (d-1)

wherein Hal is a halogen atom (a chlorine atom, a bromine atom, aniodine atom, a fluorine atom; preferably a bromine atom or an iodineatom), and R₁ and R₂ are as defined above.

In this step, compound (3) is obtained by reacting 1-5 mol of compound(2) with 1 mol of compound (1). This step is performed in the presenceof a base in a solvent that does not adversely influence the reaction.

Examples of such base include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogen carbonate, potassiumcarbonate and the like; organic bases such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like;metal hydrides such as potassium hydride, sodium hydride and the like;alkali metal alkoxides such as sodium methoxide, sodium ethoxide,potassium tert-butoxide etc., and the like.

Examples of such solvent include halogenated hydrocarbons such aschloroform, dichloromethane and the like; and nonpolar organic solventssuch as 1,4-dioxane, tetrahydrofuran and the like. These solvents may beused in a mixture of two or more kinds thereof at an appropriate ratio.Preferred is tetrahydrofuran.

The reaction temperature is generally 20° C. to 150° C., preferably 50°C. to 100° C. The reaction time is generally 1-30 hr.

Step (d-2)

wherein each symbol is as defined above.

In this step, 0.3-5 mol of compound (4) is reacted with 1 mol ofcompound (5) to give compound (6). This step is performed in thepresence of a base similar to those used in step (d-1) in a solvent thatdoes not adversely influence the reaction. Compound (I) wherein R^(a) isa group represented by the formula (a) wherein R₃ is the formula (I′)can be synthesized by reacting 0.5-5 mol of compound (6) with 1 mol ofcompound (II), followed by a reduction step.

Step (e)

wherein each group is as defined above.

In this step, 0.2-5 mol of compound (8) is reacted with 1 mol ofcompound (7) to give compound (9), and the hydroxyl group of compound(9) is substituted by halogen to give compound (10). The reaction ofcompound (7) with compound (8) is performed in the presence of a base ina solvent that does not adversely influence the reaction.

Examples of such base include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogen carbonate, potassiumcarbonate and the like; organic bases such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like;metal hydrides such as potassium hydride, sodium hydride and the like;alkali metal alkoxides such as sodium methoxide, sodium ethoxide,potassium tert-butoxide etc., and the like.

Examples of such solvent include aromatic hydrocarbons such as benzene,toluene, xylene and the like; nitriles such as acetonitrile,propionitrile and the like; ethers such as tetrahydrofuran, 1,4-dioxane,diethyl ether and the like; ketones such as acetone, 2-butanone and thelike; halogenated hydrocarbons such as chloroform, dichloromethane andthe like; amides such as N,N-dimethylformamide and the like; sulfoxidessuch as dimethyl sulfoxide etc., and the like. These solvents may beused in a mixture of two or more kinds thereof at an appropriate ratio.Preferred is dimethylformamide. The amount of the solvent to be used ispreferable 2- to 50-fold volume relative to compound (7).

The reaction temperature is generally 20° C. to 150° C., preferably 50°C. to 100° C. The reaction time is generally 1-30 hr.

The step of substituting the hydroxyl group of compound (9) to halogento give compound (10) can be performed by reacting compound (9) withtriphenylphosphine and halogen source in a solvent that does notadversely influence the reaction. This step is preferably performed inthe presence of imidazole. Examples of the halogen source include carbontetrachloride, hexachloroacetone, triphosgene (chlorine source), carbontetrabromide (bromine source), iodomethane, iodine (iodine source) andthe like. The amount of triphenylphosphine to be used is preferably0.1-5 mol per 1 mol of compound (9), and the amount of the halogensource to be used is preferably 1-5 mol per 1 mol of compound (9). Whenimidazole is used, the amount thereof to be used is preferably 0.1-5 molper 1 mol of compound (9).

Examples of such solvent include aromatic hydrocarbons such as benzene,toluene, xylene and the like; nitriles such as acetonitrile,propionitrile and the like; ethers such as tetrahydrofuran, 1,4-dioxane,diethyl ether and the like; ketones such as acetone, 2-butanone and thelike; halogenated hydrocarbons such as chloroform, dichloromethane andthe like; amides such as N,N-dimethylformamide and the like; sulfoxidessuch as dimethyl sulfoxide etc. and the like. These solvents may be usedin a mixture of two or more kinds thereof at an appropriate ratio.Preferred is toluene. The amount of the solvent to be used is preferably3- to 50-fold volume relative to compound (9).

The reaction temperature is generally 30° C. to 150° C., preferably 40°C. to 120° C. The reaction time is generally 0.5-24 hr.

Step (f)

In this step, 1-5 mol of a halogenating agent (a chlorinating agent suchas acetyl chloride, thionyl chloride and the like, a brominating agentsuch as acetyl bromide, phosphorus tribromide, diphenylphosphine/bromineetc., and the like) is reacted with 1 mol of compound (11) to givecompound (12). This reaction is performed in a solvent that does notadversely influence the reaction.

Examples of such solvent include halogenated hydrocarbons such aschloroform, dichloromethane and the like; aromatic hydrocarbons such asbenzene, toluene, xylene and the like; ethers such as 1,4-dioxane,diethyl ether and the like; and the like. These solvents may be used ina mixture of two or more kinds thereof at an appropriate ratio.Preferred are chloroform and N,N-dimethylformamide. The amount of thesolvent to be used is preferably 2- to 50-fold volume relative tocompound (11).

The reaction temperature is generally 0° C. to 100° C., preferably 0° C.to 30° C. The reaction time is generally 0.5-30 hr.

Step (g)

wherein Z′ is a hydroxyl group or a leaving group, m₃′ is 1-3,preferably 3, and R₇′ is as defined above.

In this step, compound (13) is subjected to catalytic hydrogenationreaction with a catalyst such as rhodium-carbon (Rh/C) and the like togive compound (14), and the ester moiety of compound (14) is furtherreduced to give compound (III) wherein Z′ is a hydroxyl group. This stepalso encompasses a step of obtaining compound (III) wherein Z′ is aleaving group by conversion of a hydroxyl group to a halogen group, analkylsulfonyloxy group optionally substituted by one or more halogenatoms (e.g., methanesulfonyloxy group etc.), an optionally substitutedarylsulfonyloxy group (e.g., p-toluenesulfonyloxy group etc.) and thelike. This reaction is performed in a solvent that does not adverselyinfluence the reaction.

The “alkyl” or “aryl” in the “alkylsulfonyloxy group optionallysubstituted by one or more halogen atoms” and “arylsulfonyloxy group” isa group defined above, and the “substituent” of the “optionallysubstituted arylsulfonyloxy group” is a halogen atom, an alkyl grouphaving a carbon number of 1 to 6, which is optionally substituted by oneor more halogen atoms, an alkoxy group having a carbon number of 1 to 6and the like.

Examples of the reducing agent to be used for the reduction reactioninclude metal hydride (sodium borohydride, lithium borohydride, sodiumcyanoborohydride, sodium triacetoxyborohydride, dibutylaluminum hydride,aluminum hydride, lithium aluminum hydride etc.) and the like. Of these,dibutylaluminum hydride and the like are preferable.

The reaction is performed in a solvent that does not influence thereaction. Examples of the solvent include alcohols such as methanol,ethanol and the like; ethers such as diethyl ether, tetrahydrofuran,dioxane and the like; aromatic hydrocarbons such as toluene, xylene andthe like; and a mixture thereof. Of these, tetrahydrofuran, toluene andthe like are preferable.

The reaction temperature is generally −10° C. to 100° C., preferably 0°C. to 70° C., and the reaction time is generally 1-24 hr, preferably 2-5hr.

Examples of the reagent to be used for the conversion to the leavinggroup include, besides the chlorinating agents and the brominatingagents exemplified in the above-mentioned step (f), alkylsulfonylatingagents such as methanesulfonyl chloride, trifluoromethanesulfonylchloride and the like, arylsulfonylating agents such as benzenesulfonylchloride, p-toluenesulfonyl chloride etc., and the like. Of these, anarylsulfonylating agent is preferable.

The reaction is performed in a solvent that does not influence thereaction. Examples of the solvent include halogenated hydrocarbons suchas chloroform, dichloromethane and the like; aromatic hydrocarbons suchas benzene, toluene, xylene and the like; nitriles such as acetonitrile,propionitrile and the like; ethers such as tetrahydrofuran, 1,4-dioxane,diethyl ether and the like. Of these, halogenated hydrocarbons such aschloroform and the like are preferable.

The reaction is preferably performed in the presence of 1-5 mol of anorganic base such as pyridine and the like and 0.05-0.8 mol of anN,N-dimethyl-4-aminopyridine catalyst, per 1 mol of compound (15).

The reaction temperature is generally 0-100° C., preferably 0-70° C.,and the reaction time is generally 1-24 hr, preferably 2-5 hr.

Using compounds (3), (6), (10), (12) and (16) obtained in steps (d-1),(d-2), (e), (f) and (g), the reaction of the above-mentioned step (a)can be performed to give compound (IIa), which is a useful intermediatefor the production of the compound of the present invention. In thescheme, the carbon number of aliphatic hydrocarbon group, the kind ofhalogen atom, reaction reagents and the like are shown for the sake ofconvenience, and can be appropriately changed within the scope of theabove-mentioned definitions.

[Organic Synthesis Reaction]

The compound of the present invention can be used as a reagent toprotect a carboxyl group and the like, that is, a protecting reagent foramino acid or peptide, in organic synthesis reactions, preferablypeptide synthesis and the like. Specifically, it is preferablyintroduced as a protecting group (anchor) of C-terminal functionalgroups such as a carboxyl group, a carboxamide group, a thiol group andthe like, and side chain functional groups (hereinafter to be referredto as C-terminal etc.). When using as a protecting reagent, the compoundmay be activated to allow reaction with a substituent to be protected,or may be converted to an equivalent to allow reaction. The “organiccompound protected by the benzylic compound of the present invention” ishereinafter sometimes referred to as a “benzylic compound adduct”.

The benzylic compound of the present invention can be used as aprotecting reagent (anchor) for various organic synthesis reactions. Forexample, the following steps can be performed.

-   step (i) a step of dissolving the compound of the present invention    in soluble solvent (dissolution step),-   step (ii) a step of bonding the compound of the present invention    dissolved in soluble solvent as obtained in the above-mentioned step    to a reaction substrate (bonding step),-   step (iii) a step of precipitating the bonded product obtained in    the above-mentioned step (precipitation step), and-   step (iv) a step of redissolving the bonded product obtained in the    above-mentioned step or a product resulting from the reaction in a    soluble solvent, and removing the anchor from the bonded product or    the resulting product (deprotection step).-   Step (i) (Dissolution Step)

In this step, the compound of the present invention is dissolved in asoluble solvent.

As the solvent, a general organic solvent can be used. Since superiorreactivity can be expected when the solubility in the solvent is higher,a solvent in which the compound of the present invention shows highsolubility is preferably selected. Specifically, halogenated hydrocarbonsuch as chloroform, dichloromethane and the like; and a nonpolar organicsolvent such as 1,4-dioxane, tetrahydrofuran and the like can bementioned. These solvents may be used in a mixture of two or more kindsthereof at an appropriate ratio. In addition, the above-mentionedhalogenated hydrocarbons and nonpolar organic solvent may be mixed witharomatic hydrocarbons such as benzene, toluene, xylene and the like;nitriles such as acetonitrile, propionitrile and the like; ketones suchas acetone, 2-butanone and the like; amides such asN,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide and the like at an appropriate ratio and used as long as thecompound of the present invention is dissolved.

Step (ii) (Bonding Step)

In this step, the compound of the present invention dissolved in asoluble solvent, which is obtained in the above-mentioned step (i), isbonded to a reaction substrate.

Here, the reaction substrate has a —COOH group of protected amino acidand the like, and the amount of the reaction substrate to be used is1-10 mol, preferably 1-5 mol, per 1 mol of the compound of the presentinvention.

When Y is a hydroxyl group, an ester bond can be formed by adding acondensing agent into a solvent that does not influence the reaction inthe presence of a dimethylaminopyridine catalyst.

When Y is a group NHR, an amide bond can be formed by adding acondensing agent in the presence of a condensation additive(condensation promoter) such as 1-hydroxybenzotriazole (HOBt), ethyl1-hydroxy-1H-1,2,3-triazole-5-carboxylate (HOCt),1-hydroxy-7-azabenzotriazole (HOAt) and the like.

The amount of the condensing additive to be used is preferably 0.05-1.5mol per 1 mol of the compound of the present invention.

Examples of the condensing agent include dicyclohexylcarbodiimide (DCC),diisopropylcarbodiimide (DIC),N-ethyl-N′-3-dimethylaminopropylcarbodiimide and hydrochloride thereof(EDC HCl), hexafluorophosphoric acid(benzotriazol-1-yloxy)tripyrrolizinophosphonium (PyBop),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), 1-[bis(dimethylamino)methylene]-5-chloro-1H-benzotriazolium3-oxide hexafluorophosphate (HCTU),O-benzotriazole-N,N,N′,N′-tetramethyluronium hexafluoroborate (HBTU),and the like.

The amount of the condensing agent to be used is 1-10 mol, preferably1-5 mol, per 1 mol of the compound of the present invention.

Examples of the solvent include aromatic hydrocarbons such as toluene,xylene and the like; ethers such as diethyl ether, tetrahydrofuran,dioxane and the like; halogenated hydrocarbons such as chloroform,dichloromethane etc., and the like, and a mixture thereof. Of these,toluene, tetrahydrofuran and the like are preferable.

The reaction temperature is generally −10° C. to 30° C., preferably 0°C. to 20° C., and the reaction time is generally 1-30 hr.

For confirmation of the progress of the reaction, a method similar togeneral liquid phase organic synthesis reaction can be applied. That is,thin layer silica gel chromatography, high performance liquidchromatography and the like can be used to track the reaction.

Step (iii) (Precipitation Step)

In this step, the bonded product obtained in the above-mentioned step(ii), or a product obtained by dissolving the bonded product in asoluble solvent and performing a desired organic synthesis reaction isisolated by changing the solvent in which the bonded product or theresulting product is dissolved (e.g., change of solvent composition,change of solvent kind) to allow precipitation. That is, the reaction isperformed under the conditions where the bonded product is dissolvedand, after the reaction, the solvent is evaporated, and then substitutedto allow precipitation of the bonded product and remove impurities. Asthe substitution solvent, polar organic solvents such as methanol,acetonitrile, and the like are used. That is, the reaction is performedunder conditions where the compound can be dissolved and, for solventsubstitution after the reaction, halogenated solvents, THF and the likeare used for dissolution and polar organic solvents such as methanol,acetonitrile and the like are used for precipitation.

Step (iv) (Deprotection Step)

In this step, the protecting reagent (anchor) derived from the compoundof the present invention is finally removed from the bonded product orresulting product isolated by precipitation in the above-mentioned step(iii) to give the object compound.

An anchor to be removed here is a group represented by the formula(I-d):

wherein each group is as defined above.

When Y is a hydroxyl group, it reacts with —COOH of the initial reactionsubstrate to form an ester bond. After deprotection, the C-terminal ofpeptide becomes —COOH. On the other hand, when Y is an —NHR group, the—COOH group of the reaction substrate becomes an amide bond and, byremoval of the anchor, the C-terminal is converted to a —CONHR group.

When only an anchor wherein Y is a hydroxyl group needs to beselectively removed, an anchor wherein OR^(a) is present at the2-position or 4-position on the benzene ring is used as the compound ofthe present invention, and the deprotection is preferably performed byan acid treatment. Examples of the acid to be used includetrifluoroacetic acid (hereinafter to be referred to as TFA),hydrochloric acid, sulfuric acid, methanesulfonic acid,p-toluenesulfonic acid and the like, with preference given to TFA. Thedeprotection is preferably performed under solution conditions using asolution such as chloroform, dichloromethane and THF, having an acidconcentration of 0.1% -5%.

It is also possible to remove an anchor wherein Y is a hydroxyl group or—NHR group simultaneously with other peptide-protecting group. In thiscase, a method conventionally used in the pertinent field, particularlypeptide synthesis, is used, with preference given to a method includingaddition of an acid and the like. As an acid, TFA, hydrochloric acid,sulfuric acid, mesylic acid, tosylic acid, trifluoroethanol,hexafluoroisopropanol and the like can be used. Of these, TFA isparticularly preferable.

The amount of the acid to be used is appropriately determined accordingto the kind of the acid to be used, and an amount suitable for removingthe anchor is used. The amount that can be used is 3-100 mol, preferably5-50 mol, per 1 mol of the bonded product. When an acid is used,trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate,BF₃ Et₂O and the like can also be added as a further strong acid source.

The reaction temperature is generally 0° C. to 80° C., preferably 0° C.to 30° C. The reaction time is generally 0.5-24 hr.

By utilizing the above-mentioned steps, peptide can be produced. Thebenzylic compound of the present invention can be mainly used as, but isnot limited to, a protecting reagent for C-terminal of amino acid orpeptide and the like. In addition, since the benzylic compound of thepresent invention wherein Y is a hydroxyl group can be converted to acorresponding chloroformate form by a method conventionally used in thepertinent field, for example, reaction with phosgene, the chloroformateform can also be used as a protecting reagent of N-terminal and thelike.

A method of producing a peptide utilizing the above-mentioned steps,comprising the following steps;

-   (1) a step of obtaining C-protected amino acid or C-protected    peptide, comprising condensing the benzylic compound of the present    invention with the C-terminal of N-protected amino acid or    N-protected peptide (C-terminal protection step),-   (2) a step of removing a temporary protecting group of the    N-terminal of the amino acid or peptide obtained in the    above-mentioned step (deprotection step of N-terminal),-   (3) a step of condensing the N-terminal of the amino acid or peptide    obtained in the above-mentioned step with N-protected amino acid or    N-protected peptide (peptide chain elongation step), and-   (4) a step of precipitating the peptide obtained in the    above-mentioned step (precipitation step).

Step (1) (C-Terminal Protection Step)

In this step, the benzylic compound of the present invention iscondensed with the C-terminal of N-protected amino acid or N-protectedpeptide to give C-protected amino acid or C-protected peptide, i.e.,benzylic compound adduct. For example, the step can be performedaccording to the above-mentioned binding step.

In the present invention, the “N-protected amino acid” and “N-protectedpeptide” mean amino acid and peptide wherein amino group is protectedand carboxyl group is unprotected, and may be referred to as “P-AA-OH”(P is amino-protecting group (or temporary protecting group on demand)).

wherein P is an amino-protecting group, AA is a group derived from aminoacid, Y′ is O or NR and other symbols are as defined above.

The condensation reaction of the benzylic compound of the presentinvention and C-terminal of N-protected amino acid or N-protectedpeptide is preferably performed in a solvent that does not influence thereaction. For example, the reaction is performed in the presence of acondensing agent when Y is a hydroxyl group or —NHR group, and an esterbond is formed when Y is hydroxyl, and amide bond is formed when Y is an—NHR group. Examples of the condensing agent includedicyclohexylcarbodiimide, diisopropylcarbodiimide,N-ethyl-N′-3-dimethylaminopropylcarbodiimide and a hydrochloride thereof(EDC.HCl), and the like. An ester bond forming reaction is performed inthe presence of dimethylaminopyridine, and an amide bond formingreaction is performed in the presence of a condensation additive such asHOBt, HOCt and the like.

Examples of the solvent to be used for the step include halogenatedhydrocarbons such as chloroform, dichloromethane and the like; andnonpolar organic solvents such as 1,4-dioxane, tetrahydrofuran and thelike. These solvents may be used in a mixture of two or more kindsthereof at an appropriate ratio, and preferred is chloroform. The amountof the solvent to be used is preferably 2- to 50-fold volume relative tothe benzylic compound of the present invention.

The reaction temperature is generally −10° C. to 40° C., preferably 0°C. to 30° C. The reaction time is generally 1-70 hr.

Step (2) (N-Terminal Deprotection Step)

In this step, the temporary protecting group of the N-terminal of aminoacid or peptide obtained in the above-mentioned step (1) is removed.

As the temporary protecting group of the N-terminal, the below-mentionedamino-protecting groups generally used in the technical field of peptidechemistry and the like are usable. In the present invention, atert-butoxycarbonyl group (hereinafter to be also referred to as Bocgroup), a benzyloxycarbonyl group and/or a 9-fluorenylmethoxycarbonylgroup (hereinafter to be also referred to as Fmoc group) are/ispreferably used.

While the deprotection conditions are appropriately selected dependingon the kind of the temporary protecting group, a group that can beremoved under conditions different from removal of the protectingreagent derived from the compound of the present invention ispreferable. For example, Fmoc group can be removed by a treatment with abase, and Boc group can be removed by a treatment with an acid. Thereaction is performed in a solvent which does not influence thereaction.

Examples of the base include dimethylamine, diethylamine and the like.Examples of the solvent include halogenated hydrocarbons such aschloroform, dichloromethane, and the like; aromatic hydrocarbons such astoluene, xylene, and the like; ethers such as diethyl ether,tetrahydrofuran, dioxane, and the like; nitriles such as acetonitrileand the like, and a mixture thereof.

Step (3) (Peptide Chain Elongation Step)

In this step, the N-terminal of amino acid or peptide deprotected inN-terminal in step (2) is condensed with N-protected amino acid orN-protected peptide.

This step is performed by using the condensing agent, condensationadditive and the like described in the aforementioned step (1) and underpeptide synthesis conditions generally used in the field of peptidechemistry.

Step (4) (Precipitation Step)

This step is performed in the same manner as in the precipitation stepin the above-mentioned step (iii).

In the production method of the peptide of the present invention, theN-protected amino acid or N-protected peptide obtained in step (4) canbe subjected to steps (5)-(7) in a desired number of repeats:

-   (5) a step of removing the temporary protecting group of N-terminal    of the peptide obtained in the precipitation step,-   (6) a step of condensing N-protected amino acid or N-protected    peptide with N-terminal of the peptide obtained in the    above-mentioned step, and-   (7) a step of precipitating the peptide obtained in the    above-mentioned step.

Step (5)

The step is performed in the same manner as in the deprotection step ofN-terminal in step (2).

Step (6)

This step is performed in the same manner as in the peptide chainelongation step of step (3).

Step (7)

This step is performed in the same manner as in the precipitation stepof step (iii).

In the production method of the peptide of the present invention, a stepof deprotecting the C-terminal of the peptide, wherein the C-terminal isprotected with the benzylic compound, may be further contained after theprecipitation step of step (4) or step (7). For example, the step can beperformed according to the above-mentioned step (iv) for deprotection ofthe anchor of the present invention.

When the organic synthesis reaction or peptide synthesis reaction of thepresent invention contains multi-steps, the aforementioned precipitationstep may be appropriately omitted as long as the reaction in the nextstep is not influenced.

In each reaction, when the starting compound has a hydroxy group, anamino group, a carboxy group or a carbonyl group (particularly whenamino acid or peptide has a functional group in the side chain), aprotecting group generally used in the peptide chemistry and the likemay be introduced into these groups, and the object compound can beobtained by removing the protecting group as necessary after thereaction.

Examples of the hydroxyl-protecting group include (C₁-C₆)alkyl group(e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenylgroup, trityl group, (C₇-C₁₀)aralkyl group (e.g., benzyl), formyl group,(C₁-C₆)alkyl-carbonyl group (e.g., acetyl, propionyl), benzoyl group,(C₇-C₁₀)aralkyl-carbonyl group (e.g., benzylcarbonyl),2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, silyl group (e.g.,trimethylsilyl, triethylsilyl, dimethylphenylsilyl,tert-butyldimethylsilyl, tert-butyldiethylsilyl), (C₂-C₆)alkenyl group(e.g., 1-allyl) and the like. These groups are optionally substituted by1 to 3 substituents selected from a halogen atom (e.g., fluorine,chlorine, bromine, iodine), a (C₁-C₆)alkyl group (e.g., methyl, ethyl,propyl), a (C₁-C₆)alkoxy group (e.g., methoxy, ethoxy, propoxy), a nitrogroup and the like.

Examples of the amino-protecting group include formyl group,(C₁-C₆)alkyl-carbonyl group (e.g., acetyl, propionyl),(C₁-C₆)alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, Bocgroup), benzoyl group, (C₇-C₁₀)aralkyl-carbonyl group (e.g.,benzylcarbonyl), (C₇-C₁₉)aralkyloxy-carbonyl group (e.g.,benzyloxycarbonyl, Fmoc group), trityl group, phthaloyl group,N,N-dimethylaminomethylene group, silyl group (e.g., trimethylsilyl,triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl,tert-butyldiethylsilyl), (C₂-C₆)alkenyl group (e.g., 1-allyl) and thelike. These groups are optionally substituted by 1 to 3 substituentsselected from a halogen atom (e.g., fluorine, chlorine, bromine,iodine), a (C₁-C₆)alkoxy group (e.g., methoxy, ethoxy, propoxy), a nitrogroup and the like.

Examples of the carboxy-protecting group include (C₁-C₆)alkyl group(e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl),(C₇-C₁₀)aralkyl group (e.g., benzyl), phenyl group, trityl group, silylgroup (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl,tert-butyldimethylsilyl, tert-butyldiethylsilyl,tert-butyldiphenylsilyl), (C₂-C₆)alkenyl group (e.g., 1-allyl) and thelike can be mentioned. These groups are optionally substituted by 1 to 3substituents selected from a halogen atom (e.g., fluorine, chlorine,bromine, iodine), a (C₁-C₆)alkoxy group (e.g., methoxy, ethoxy,propoxy), a nitro group and the like.

Examples of the carbonyl-protecting group include cyclic acetal (e.g.,1,3-dioxane), acyclic acetal (e.g., di-(C₁-C₆)alkylacetal) and the like.

These protecting groups can be removed by a method known per se, forexample, the method described in Protective Groups in Organic Synthesis,John Wiley and Sons (1980) and the like. or example, a method usingacid, base, ultraviolet rays, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate,trialkylsilylhalide (e.g., trimethylsilyliodide, trimethylsilylbromideand the like) and the like, a reduction method and the like are used.

[Kit for Liquid Phase Synthesis of Peptide]

The present invention also provides a kit for liquid phase synthesis ofpeptide, which contains the compound of the present invention as anessential constituent component. The kit may contain, besides thecompound of the present invention, other components necessary for liquidphase synthesis reaction of peptide, for example, various solvents usedfor the reaction, amino acid (or peptide) to be the starting materialand the like. When desired, a manual of liquid phase synthesis ofpeptide using the compound of the present invention can also beattached.

EXAMPLES

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof. The reagents, apparatuses and materials used in the presentinvention are commercially available unless otherwise specified. In thepresent specification, when amino acid and the like are indicated byabbreviation, each indication is based on the abbreviation of theIUPAC-IUB Commission on Biochemical Nomenclature or conventionalabbreviations in the art.

Example 1 Synthesis of 4-(12′-docosyloxy-1′-dodecyloxy)-2-methoxybenzylalcohol

(i) 12-Docosyloxy-1-bromododecane (1.00 g, 1.74 mmol),4-hydroxy-2-methoxybenzaldehyde (292 mg, 1.92 mmol) and potassiumcarbonate (361 mg, 2.61 mmol) were suspended in DMF (10 ml), and thesuspension was stirred at 70° C. for 2 days. The reaction mixture wascooled to room temperature, extracted with chloroform (20 ml), andwashed once with 1N hydrochloric acid (10 ml) and 3 times with water (10ml). The combined organic layers were evaporated under reduced pressure,and the residue was precipitated with methanol (10 ml) to give4-(12′-docosyloxy-1′-dodecyloxy)-2-methoxybenzaldehyde (1.05 g, 1.63mmol, 93%).

¹H-NMR (300 MHz, CDCl₃)δ: 0.88(3H, t, J=6.6 Hz, —OC₂₁H₄₂-Me),1.15-1.65(58H, br, Alkyl-H), 1.80(2H, m, Ar—O—CH₂—CH₂ —), 3.39(4H, t,J=6.6 Hz, —C₁₁H₂₂—CH₂ —O—CH₂ —C₂₁H₄₃), 3.90 (3H, s, —OMe), 4.02 (2H, t,J=6.6 Hz, Ar—O—CH₂ —), 6.44(1H, d, J=1.8 Hz, Ph, C3-H), 6.54(1H, dd,J=1.8, 8.7 Hz, Ph, C5-H), 7.79(1H, d, J=8.7 Hz, Ph, C6-H), 10.28(1H, s,Ar—CHO)

(ii) 4-(12′-Docosyloxy-1′-dodecyloxy)-2-methoxybenzaldehyde (1.02 g,1.58 mmol) was suspended in THF-MeOH (10 ml+0.5 ml), sodium borohydride(80 mg, 2.11 mmol) was added, and the suspension was stirred at 50° C.overnight. 1N Hydrochloric acid was added dropwise to the reactionmixture to quench the reaction, and the mixture was extracted withchloroform (20 ml), and washed once with 1N hydrochloric acid (10 ml)and 3 times with water (10 ml). The solvent was evaporated, and theobtained residue was precipitated with methanol (10 ml) and washed withacetonitrile to give 4-(12′-docosyloxy-1′-dodecyloxy)-2-methoxybenzylalcohol (972 mg, 1.50 mmol, 95%).

¹H-NMR (300 MHz, CDCl₃) δ: 0.88(3H, t, J=6.6 Hz, —OC₂₁H₄₂-Me),1.15-1.65(58H, br, Alkyl-H), 1.77(2H, m, Ar—O—CH₂—CH₂ —), 2.10(1H, t,J=6.3 Hz, —OH), 3.39(4H, t, J=6.9 Hz, —C₁₁H₂₂—CH₂ —O—CH₂ —C₂₁H₄₃),3.84(3H, s, —OMe), 3.95(2H, t, J=6.6 Hz, Ar—O—CH₂ —), 4.61 (2H, d, J=6.3Hz, benzyl-H), 6.43(1H, dd, J=2.1, 8.1 Hz, Ph, C5-H), 6.47(1H,d, J=2.1Hz, Ph, C3-H), 7.14(1H, d, J=8.1 Hz, Ph, C6-H)

Example 2 Synthesis of4-(12′-docosyloxy-1′-dodecyloxy)-2-methoxybenzylamine

(i) 4-(12′-Docosyloxy-1′-dodecyloxy)-2-methoxybenzaldehyde (1.07 g, 1.66mmol) was dissolved in dichloromethane (15 ml), hydroxylaminehydrochloride (344 mg, 4.80 mmol) and triethylamine (1.15 ml, 8.26 mmol)were added, and the mixture was stirred at room temperature. Afterconfirmation of disappearance of the starting material, the solvent wasevaporated under reduced pressure, and the residue was precipitated withacetonitrile to give4-(12′-docosyloxy-1′-dodecyloxy)-2-methoxybenzaldoxime (1.08 g, 1.64mmol, 98%).

¹H-NMR (300 MHz, CDCl₃) δ: 0.88(3H, t, J=6.9 Hz, —C₂₁H₄₂-Me),1.00-1.70(58H, br, m, alkyl-H), 1.70-1.85(2H, m, —O—CH₂—CH₂ —C₂₀H₄₁),3.39 (4H, t, J=6.7 Hz, —C₁₁H₂₂—CH₂ —O—CH₂ —C₂₁H₄₃), 3.83 (3H, s, —OMe),3.97(2H, t, J=6.5 Hz, Ar—O—CH₂ —C₁₁H₂₂—), 6.44(1H, d, J=2.0 Hz, C3-H),6.48(1H, dd, J=2.2, 8.6 Hz, C5-H), 7.03(1H, br, —CHNOH), 7.62(1H, d,J=8.5 Hz, C6-H), 8.41(1H, s, —CHNOH)

(ii) To 4-(12′-docosyloxy-1′-dodecyloxy)-2-methoxybenzaldoxime (780 mg,1.18 mmol) obtained in (i) were added THF (20 ml), methanol (10 ml) and10% palladium-carbon (Pd/C, 80 mg), and the mixture was stirred under ahydrogen atmosphere overnight.

The reaction mixture was filtered to remove Pd/C, and the filtrate wasconcentrated under reduced pressure. The residue was precipitated withmethanol to give 4-(12′-docosyloxy-1′-dodecyloxy)-2-methoxybenzylamine(744 mg, 1.15 mmol, 97%).

¹H-NMR (300 MHz, CDCl₃) δ: 0.88(3H, t, J=6.9 Hz, —C₂₁H₄₂-Me),1.00-1.90(60H, br, m, alkyl-H), 3.39(4H, t, J=6.9 Hz, —C₁₁H₂₂—CH₂ —O—CH₂—C₂₁H₄₃), 3.78(2H, s, Ar—CH₂ —NH₂), 3.82(3H, s, —OMe), 3.94(2H, t, J=6.5Hz, Ar—O—CH₂ —C₁₁H₂₂—), 6.41(1H, dd, J=2.2, 8.1 Hz, C5-H), 6.46(1H, d,J=2.2 Hz, C3-H), 7.10(1H, d, J=8.2 Hz, C6-H)

Example 3 Synthesis of 2-(12′-docosyloxy-1′-dodecyloxy)-4-methoxybenzylalcohol

The title compound was synthesized from 2-hydroxy-4-methoxybenzaldehydein the same manner as described for the synthesis in Example 1.

¹H-NMR (300 MHz, CDCl₃): δ0.88(3H, t, J=6.6 Hz, —OC₂₁H₄₂-Me),1.15-1.65(58H, br, Alkyl-H), 1.81(2H, m, Ar—O—CH₂—CH₂ —), 2.21(1H, br,s, —OH), 3.39(4H, t, J=6.6 Hz, —C₁₁H₂₂—CH₂ —O—CH₂ —C₂₁H₄₃), 3.80(3H, s,—OMe), 3.98(2H, t, J=6.6 Hz, Ar—O—CH₂ —), 4.61(2H, br, d, J=3.6 Hz,benzyl-H), 6.44(1H, dd, J=2.1, 8.1 Hz, Ph, C5-H), 6.45(1H, s, Ph, C3-H),7.16(1H, d, J=7.8 Hz, Ph, C6-H)

Example 4 Synthesis of 4-(12′-docosyloxy-1′-dodecyloxy)benzyl alcohol

The title compound was synthesized from 4-hydroxybenzaldehyde in thesame manner as described for the synthesis in Example 1.

¹H-NMR (300 MHz, CDCl₃): δ0.88 (3H, t, J=7.2 Hz, —OC₂₁H₄₂-Me),1.15-1.65(58H, br, Alkyl-H), 1.77(2H, m, Ar—O—CH₂—CH₂ —), 3.39(4H, t,J=6. 6 Hz, —C₁₁H₂₂—CH₂ —O—CH₂ —C₂₁H₄₃), 3.95 (2H, t, J=6. 6 Hz, Ar—O—CH₂—), 4.61(2H, d, J=4.8 Hz, benzyl-H), 6.88(2H, d, J=8.4 Hz, Ph, C3, 5-H),7.27(2H, d, J=9.6 Hz, Ph, C2,6-H)

Example 5 Synthesis of 2-docosyloxy-4-methoxybenzyl alcohol

2-Hydroxy-4-methoxybenzaldehyde (5 g, 32.9 mmol), 1-bromodocosane (16.6g, 42.7 mmol) and potassium carbonate (14.8 g, 107 mmol) were mixed withDMF (150 ml), and the mixture was stirred at 100° C. for 7 hr.Chloroform (400 ml) and 1N hydrochloric acid (300 ml) were added to thereaction mixture, and the mixture was washed. The organic layer waswashed successively with 1N hydrochloric acid and saturated brine. Theorganic layer was concentrated and slurry-washed with methanol. Theprecipitate was collected by filtration and dried under reducedpressure. The obtained dried crystals were dissolved in THF (150 ml),sodium borohydride (3.7 g) was added, and the mixture was stirred at 40°C. for 3 hr. 1N Hydrochloric acid was added to the reaction mixture, andthe mixture was concentrated. The mixture was extracted with chloroform,and washed successively with aqueous sodium hydrogen carbonate solutionand saturated brine. The organic layer was concentrated. The obtainedresidue was washed with acetonitrile, and the precipitate was collectedby filtration and dried under reduced pressure to give2-docosyloxy-4-methoxybenzyl alcohol (9.8 g).

¹H-NMR (300 MHz, CDCl₃): δ0.88(3H, t, J=6.5 Hz), 1.21-1.55(38H, m),1.76-1.85(2H, m), 3.80(3H, s), 3.98(2H, t, J=6.3 Hz), 4.62(2H, s),6.42-6.42(2H, m), 7.15(1H, d, J=7.8 Hz)

Example 6 Synthesis of4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)benzyloxy]benzyl alcohol

(i) 3,4,5-Tris(octadecyloxy)benzyl alcohol (83.0 g, 90.8 mmol) wasdissolved in chloroform (830 ml), thionyl chloride (21.6 g, 0.182 mol)was added at 0° C., and the mixture was stirred at room temperature for1.5 hr. The solvent was evaporated, and the residue was precipitatedwith acetonitrile (800 ml) to give 3,4,5-tri(octadecyloxy)benzylchloride(93.6 g) as wet crystals.

(ii) 3,4,5-Tri(octadecyloxy)benzylchloride (93.6 g, wet, <90.8 mmol),2-hydroxy-4-methoxybenzaldehyde (15.2 g, 0.10 mol) and potassiumcarbonate (31.4 g, 0.23 mol) were suspended in DMF (830 ml), and thesuspension was stirred at 80° C. overnight. The reaction mixture wasdissolved in chloroform (1600 ml), and the mixture was washed 3 timeswith 1N hydrochloric acid (800 ml), once with 5% aqueous sodium hydrogencarbonate solution (800 ml), and once with 20% brine (800 ml). Thesolvent was evaporated, and the residue was precipitated with methanol(800 ml) and washed with acetonitrile (800 ml) to give4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)benzyloxy]benzaldehyde (93.5 g,89.2 mmol, 98%).

(iii) 4-Methoxy-2-[3′,4′,5′-tris(octadecyloxy)benzyloxy]benzaldehyde(93.5 g, 89.2 mmol) was dissolved in THF-methanol (1870 ml+94 ml), andsodium borohydride (4.05 g, 107 mmol) was added at 0° C. After stirringat room temperature for 1.5 hr, 0.2N hydrochloric acid (100 ml) wasadded at 0° C. to quench the reaction. The solvent was evaporated toabout half, and dissolved in chloroform (2400 ml). The mixture waswashed twice with 0.1N hydrochloric acid (1200 ml), once with 5% aqueoussodium hydrogen carbonate solution (1200 ml), and once with 20% brine(1200 ml). The solvent was evaporated, and the residue was precipitatedwith methanol (900 ml) and washed with acetonitrile to give4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)benzyloxy]benzyl alcohol (92.4g, 88.0 mmol, 97% yield vs 3,4,5-tris(octadecyloxy)benzyl alcohol).

¹H-NMR (300 MHz, CDCl₃): δ0.88 (9H, t, J=6.3 Hz, C₁₇H₃₄—-Me), 1.15-1.40(84H, br, C3′,5′—OC₃H₆—C₁₄H₂₈—CH₃), 1.40-1.55(6H, br,C3′,4′,5′-OC₂H₄—CH₂ —C₁₅H₃₁), 1.70-1.85(6H, m, C3′,4′,5′-OCH₂—CH₂—C₁₆H₃₃), 2.18(1H, t, J=6.3 Hz, OH), 3.79(3H, s, C4-OMe), 3.90-4.03(6H,m, C3′,4′,5′-O—CH₂ —C₁₇H₃₅), 4.65 (2H, d, J=6.6 Hz, Ar—CH₂ —OH),4.97(2H, s, Ar—O—CH₂ —Ar), 6.47 (1H, dd, J=2.1, 8.1 Hz, C5-H), 6.53(1H,d, J=2.4 Hz, C3-H), 6.60(2H, s, C2′,6′-H), 7.19(1H, d, J=8.1 Hz, C6-H)

Example 7 Synthesis of 2-[3′,5′-di(docosyloxy)benzyloxy]-4-methoxybenzylalcohol

(i) 3,5-Di(docosyloxy)benzyl alcohol (500 mg, 0.66 mmol) was dissolvedin chloroform (5 ml), thionyl chloride (71 μl, 0.99 mmol) and DMF (10μl, 0.13 mmol) were added dropwise, and the mixture was stirred at roomtemperature for 1 hr. The solvent was evaporated, and the residue wasprecipitated with acetonitrile to give 3,5-di(docosyloxy)benzylchloride(505 mg, 0.65 mmol, 99%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(3H, t, J=6.6 Hz, —OC₂₁H₄₂-Me),1.20-1.60(76H, br, Alkyl-H), 1.76(2H, m, Ar—O—CH₂—CH₂ —), 3.93(4H, t,J=6.6 Hz, Ar—O—CH₂ —C₂₁H₄₃), 4.49(2H, s, benzyl-H), 6.39(1H, br, t, Ph,C4-H), 6.51(2H, d, J=2.1 Hz, Ph, C2,6-H)

(ii) 3,5-Di(docosyloxy)benzylchloride (450 mg, 0.58 mmol),2-hydroxy-4-methoxybenzaldehyde (185 mg, 1.22 mmol) and potassiumcarbonate (200 mg, 1.45 mmol) were suspended in DMF (4.5 ml), and themixture was stirred at 80° C. for 6 hr. The reaction mixture wasextracted with chloroform (20 ml), and washed 3 times with 1Nhydrochloric acid (7 ml). The solvent was evaporated and the obtainedresidue was precipitated with methanol (5 ml) to give2-[3′,5′-di(docosyloxy)benzyl]-4-methoxybenzaldehyde (502 g, 0.56 mmol,97%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(3H, t, J=6.6 Hz, —OC₂₁H₄₂-Me),1.15-1.65(76H, br, Alkyl-H), 1.76(2H, m, Ar—O—CH₂—CH₂ —), 3.84(3H, s,—OMe), 3.93(4H, t, J=6.6 Hz, Ar—O—CH₂ —C₂₁H₄₃), 5.08(2H, s, benzyl-H),6.41(1H, br, s, Ph, C3 or C5 or C4′-H), 6.49(1H, d, J=2.1 Hz, Ph, C3 orC5 or C4′-H), 6.53-6.60(3H, m, Ph, C2′,C6′-H, C3 or C5 or C4′-H),7.16(1H, d, J=7.8 Hz, Ph, C6-H)

(iii) 2-(3′,5′-Di(docosyloxy)benzyl)-4-methoxybenzaldehyde (450 mg, 0.50mmol) was dissolved in THF-EtOH (4 ml+0.5 ml), sodium borohydride (34mg, 0.90 mmol) was added, and the mixture was stirred for 3.5 hr. 1NHydrochloric acid was added dropwise to the reaction mixture to quenchthe reaction, and the mixture was extracted with chloroform (15 ml),washed once with 1N hydrochloric acid (10 ml), and 3 times with water (5ml). The solvent was evaporated, and the obtained residue wasprecipitated with methanol (5 ml) to give2-(3′,5′-di(docosyloxy)benzyl)-4-methoxybenzyl alcohol (424 mg, 0.47mmol, 94%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(3H, t, J=6.6 Hz, —OC₂₁H₄₂-Me),1.15-1.65(76H, br, Alkyl-H), 1.76(2H, m, Ar—O—CH₂—CH₂ —), 3.79(3H, s,—OMe), 3.95(4H, t, J=6.6 Hz, Ar—O—CH₂ —C₂₁H₄₃), 4.66(2H, s, Ar—CH₂ —OH),5.00(2H, s, Ar—CH₂ —O—Ar), 6.40(1H, br, t, Ph, C3 or C5 or C4′-H),6.47(1H, dd, J=2.1, 8.1 Hz, Ph, C3 or 05 or C4′-H), 6.50-6.60(3H, m, Ph,C2′,6′-H, C3 or C5 or C4′-H), 7.19(1H, d, J=8.1 Hz, Ph, C6-H)

Example 8 Synthesis of2-methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzyl alcohol

(i) To pentaerythritol (1.5 g, 11.0 mmol) were added DMF (100 ml),1-bromooctadecane (11.4 g, 34.2 mmol) and sodium hydride (60 wt %, 1.54g, 38.5 mmol), and the mixture was stirred at 100° C. for 22 hr. Thereaction mixture was cooled to room temperature, chloroform (150 ml) wasadded, and 1N hydrochloric acid (150 ml) was added further dropwise.After stirring, the aqueous layer was removed, and the organic layer wasfurther washed with 1N hydrochloric acid (100 ml) and water (100 ml).The organic layer was evaporated under reduced pressure, and the residuewas precipitated with methanol (150 ml), and the obtained precipitatewas washed with methanol (150 ml). The crude crystals were dried andpurified by silica gel column chromatography(hexane:chloroform=1:1→hexane:ethyl acetate=10:1) to give2,2,2-tris(octadecyloxymethyl)ethanol (2.21 g, 2.47 mmol, yield 23%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(3H, t, J=6.9 Hz, —OC₁₇H₃₄-Me),1.10-1.65(96H, br, C₁₈Alkyl-H), 3.12(1H, t, J=6.0 Hz, OH), 3.38(6H, t,J=6. 3 Hz, —C—(CH₂—O—CH₂ —C₁₇H₃₅)₃) 3.43 (6H, s, —C—(CH₂ —O—C₁₈H₃₇)₃),3.70(2H, d, J=5.7 Hz, HO—CH₂ —)

(ii) 2,2,2-Tris(octadecyloxymethyl)ethanol (500 mg, 560 μmol) wasdissolved in toluene (10 ml), triphenylphosphine (294 mg, 1.12 mmol),imidazole (76.2 mg, 1.12 mmol) and iodine (284 mg, 1.12 mmol) wereadded, and the mixture was stirred at 100° C. overnight. The reactionmixture was cooled to room temperature, toluene (10 ml) was added, andthe mixture was partitioned and washed three times with water (5 ml).The organic layer was evaporated under reduced pressure, and the residuewas precipitated with acetonitrile (10 ml) to give1-[3-iodo-2,2-bis(octadecyloxymethyl)propoxy]octadecane (555 mg, 553μmol, yield 98%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(3H, t, J=6.9 Hz, —OC₁₇H₃₄-Me),1.10-1.65(96H, br, C18Alkyl-H), 3.33(6H, s, —C—(CH₂ —O—C₁₈H₃₇)₃),3.38(6H, t, J=6.3 Hz, —C—(CH₂—O—CH₂ —C₁₇H₃₅)₃), 3.48(2H, s, I—CH₂ —)

(iii) 4-Hydroxy-2-methoxybenzaldehyde (136 mg, 894 μmol) was dissolvedin DMF (10 ml), 1-[3-iodo-2,2-bis(octadecyloxymethyl)propoxy]octadecane(600 mg, 598 μmol) and potassium carbonate (165 mg, 1.19 mmol) wereadded, and the mixture was stirred at 130° C. for 3 days. The reactionmixture was cooled to room temperature, 1N hydrochloric acid (10 ml) andchloroform (10 ml) were added, and the mixture was stirred. The aqueouslayer was removed, and the organic layer was further washed twice withpurified water (10 ml). The organic layer was evaporated under reducedpressure, and the residue was precipitated with methanol to give crudecrystals of2-methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzaldehyde (592mg, 96%). The obtained crude crystals were purified by silica gel columnchromatography (chloroform-hexane=2:1-chloroform→hexane-ethylacetate=10:1).

¹H-NMR (300 MHz, CDCl₃): δ0.88(3H, t, J=6.9 Hz, —OC₁₇H₃₄-Me),1.10-1.60(96H, br, C18Alkyl-H), 3.38(6H, t, J=6.3 Hz, —C—(CH₂—O—CH₂—C₁₇H₃₅)₃), 3.48 (6H, s, —C— (CH₂ —O—C₁₈H₃₇)₃), 3.90 (3H, s, —OMe),4.03(2H, s, Ar—O—CH₂ —), 6.43(1H, d, J=2.1 Hz, Ph C3-H), 6.57(1H, dd,J=2.1, 9.0 Hz, Ph C5-H), 7.78(1H, d, J=9.0 Hz, Ph C6-H), 10.28(1H, s,Ar—CHO)

(iv) 2-Methoxy-4-(2′,2′,2′-tris(octadecyloxymethyl)ethoxy)benzaldehyde(288 mg, 280 μmol) was dissolved in THF (3 ml), methanol (0.3 ml) andsodium borohydride (31.8 mg, 841 μmol) were added, and the mixture wasstirred at 60° C. for 2 hr. The reaction mixture was cooled to roomtemperature, 1N hydrochloric acid (5 ml) and chloroform (5 ml) wereadded, and the mixture was stirred. The aqueous layer was removed, andthe organic layer was further washed twice with purified water (5 ml).The organic layer was evaporated under reduced pressure, and the residuewas azeotropically distilled with acetonitrile and dried in vacuo togive 2-methoxy-4-(2′,2′,2′-tris(octadecyloxymethyl)ethoxy)benzylalcohol.

¹H-NMR (300 MHz, CDCl₃): δ0.88(3H, t, J=6.6 Hz, —OC₁₇H₃₄-Me),1.10-1.60(96H, br, C18Alkyl-H), 2.09(1H, br, OH), 3.38(6H, t, J=6.3 Hz,—C—(CH₂—O—CH₂ —CH₁₇H₃₅)₃), 3.48 (6H, s, —C—(CH₂ —O—C₁₈H₃₇)₃), 3.85(3H,s, —OMe), 3.95(2H, s, Ar—O—CH₂—), 4.60(1H, d, J=5.1 Hz, benzyl-H),6.40-6.55(2H, m, Ph C3, 5-H), 6.57(1H, dd, J=2.1, 9.0 Hz, Ph C5-H),7.12(1H, d, J=8.7 Hz, Ph C6-H)

Example 9 Synthesis of2-methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzylamine

(i) 2-Methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzaldehyde(50 mg, 0.049 mmol) was dissolved in dichloromethane (1 ml),hydroxylamine hydrochloride (18 mg, 0.26 mmol) and triethylamine (51 μl,0.37 mmol) were added, and the mixture was stirred at room temperaturefor 4 hr. The solvent was evaporated, and the residue was precipitatedwith acetonitrile to give2-methoxy-4-[2,2,2-tris(octadecyloxymethyl)ethoxy]benzaldoxime (43 mg,0.041 mmol, 85%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(3H, t, J=6.9 Hz, —OC₁₇H₃₄-Me),1.10-1.60(96H, br, C18Alkyl-H), 3.38(6H, t, J=6.3 Hz, —C—(CH₂—O—CH₂—C₁₇H₃₅)₃) 3.48 (6H, s, —C—(CH₂ —O—C₁₈H₃₇)₃) 3.83 (3H, s, —OMe),3.98(2H, s, Ar—O—CH₂ —), 6.43(1H, d, J=2.1 Hz, Ph C3-H), 6.52(1H, dd,J=2.1, 8.7 Hz, Ph C5-H), 6.94(1H, br, N—OH), 7.61(1H, d, J=8.7 Hz, PhC6-H), 8.41(1H, s, —CH═N—)

(ii) 2-Methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzaldoxime(40 mg, 0.038 mmol) was dissolved in THF (1 ml), diisobutylaluminumhydride (DIBAL)-toluene solution (127 μl, 0.13 mmol) was added dropwise,and the mixture was stirred for 2.5 hr. 1N Hydrochloric acid (2 ml) wasadded dropwise to the reaction mixture to quench the reaction, and themixture was extracted with chloroform (2 ml) and washed with 10% aqueoussodium carbonate solution (1 ml). The solvent was evaporated, andacetonitrile (1 ml) was added to the residue. The precipitate wascollected by filtration, and purified by silica gel chromatography togive 2-methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzylamine(43 mg, 0.041 mmol, 85%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(3H, t, J=6.9 Hz, —OC₁₇H₃₄-Me),1.10-1.60(96H, br, C18Alkyl-H), 2.82(2H, d, J=5.4 Hz, —NH₂ ), 3.38(6H,t, J=6.3 Hz, —C—(CH₂—O—CH₂ —C₁₇H₃₅)₃), 3.48 (6H, s, —C—(CH₂—O—C₁₈H₃₇)₃), 3.82(3H, s, —OMe), 3.70-4.00(2H, m, Ar—O—CH₂—, benzyl-H),6.40-6.50(3H, m, Ph C3,5,6-H)

Example 10 Synthesis of4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzylalcohol

(i) To methyl 3,4,5-tris(octadecyloxy)benzoate (1 g, 10.6 mmol) wasadded cyclohexane, 5% rhodium-carbon (0.8 g) was added, andhydrogenation was performed at 80° C., 10 atm. Tetrahydrofuran (10 ml)was added, and the catalyst was filtered off. The filtrate wasconcentrated, methanol (8 ml) was added, and the mixture was stirred.The precipitate was collected by filtration and dried to give methyl3,4,5-tris(octadecyloxy)cyclohexylcarboxylate (820 mg, 0.87 mmol, 82%).

¹H-NMR (300 MHz, CDCl₃): δ0.89(9H, t, J=6.9 Hz, C₁₇H₃₄-Me),1.25-1.44(90H, m), 1.52-1.60(6H, m), 1.86-1.94(4H, m), 2.23(1H, m),3.09-3.14(2H, m), 3.41-3.47(4H, m), 3.64-3.68(5H, m), 3.86(1H, s)

(ii) Methyl 3,4,5-tris(octadecyloxy)cyclohexylcarboxylate (70.0 g, 73.9mmol) was dissolved in THF (1050 ml), and DIBAL (1.0 mol/L toluenesolution, 200 ml, 200 mmol) was added dropwise at 0° C. over 40 minunder a nitrogen atmosphere. After stirring at room temperature for 2hr, 0.2N hydrochloric acid (50 ml) was added dropwise at 0° C. to quenchthe reaction. The solvent was evaporated to about half, and the residuewas dissolved in chloroform (700 ml). The mixture was washed three timeswith 1N hydrochloric acid (300 ml), once with 5% aqueous sodium hydrogencarbonate solution (300 ml), and once with 20% brine (300 ml). Thesolvent was evaporated, and the residue was precipitated with methanol(700 ml), and washed with acetonitrile to give3,4,5-tris(octadecyloxy)cyclohexylmethyl alcohol (68.2 g, 74.2 mmol,100%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(9H, t, J=6.9 Hz, C₁₇H₃₄-Me),1.15-1.80(101H, br, m, C1-H, C2,6-H₂ , C3,4,5-OCH₂—C₁₆ H₃₂ —CH₃),3.10-3.20(2H, br, m, C3,5-H), 3.35-3.60(6H, m, C3,5-O—CH₂ —C₁₇H₃₅,Cy-CH₂ —OH), 3.67(2H, t, J=6.6 Hz, C4-O—CH₂ —C₁₇H₃₅), 3.90(1H, s, C4-H)

(iii) 3,4,5-Tris(octadecyloxy)cyclohexylmethyl alcohol (68.5 g, 74.5mmol) was dissolved in chloroform (700 ml), pyridine (26.9 ml, 0.33mol), DMAP (903 mg, 7.39 mmol) and p-toluenesulfonyl chloride (44.9 g,0.236 mol) were added, and the mixture was stirred for 5 days. Thesolvent was evaporated, and the residue was precipitated withacetonitrile (700 ml) and washed with acetonitrile (700 ml) to give3,4,5-tris(octadecyloxy)cyclohexylmethyl tosylate (76.9 g, 71.6 mmol,96%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(9H, t, J=6.9 Hz, C₁₇H₃₄-Me),1.15-1.80(101H, br, m, C1-H, C2,6-H₂ —, C3,4,5-OCH₂—C₁₆ H₃₂ —CH₃),2.45(3H, s, Me(Ts)), 3.05-3.12(2H, br, m, C3,5-H), 3.30-3.55(4H, m,C3,5-O—CH₂—C₁₇H₃₅), 3.62 (2H, t, J=6.6 Hz, C4-O—CH₂ —C₁₇H₃₅),3.80-3.90(3H, m, C4-H, Cy-CH₂ —OTs), 7.34(2H, d, J=8.1 Hz, C2′,6′-H),7.78(2H, d, J=8.4 Hz, C3′,5′-H)

(iv) 3,4,5-Tris(octadecyloxy)cyclohexylmethyl tosylate (76.9 g, 71.6mmol), 2-hydroxy-4-methoxybenzaldehyde (16.9 g, 0.11 mol) and potassiumcarbonate (25.6 g, 0.18 mol) were suspended in DMF (700 ml), and themixture was stirred at 80° C. overnight.

The reaction mixture was dissolved in chloroform (700 ml), washed twicewith 0.5N hydrochloric acid (300 ml), once with 5% aqueous sodiumhydrogen carbonate solution (300 ml), and once with pure water (300 ml).The solvent was evaporated, and the residue was precipitated withmethanol (700 ml) to give4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzaldehyde(73.56 g, 69.8 mmol, 97%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(9H, t, J=6.9 Hz, C₁₇H₃₄-Me), 1.15-1.90(101H, br, m, C1′-H, C2′,6′-H ₂, C3′,4′,5′-OCH₂—C₁₆ H₃₂ —CH₃),3.15-3.25(2H, br, m, C3′,5′-H), 3.35-3.55(4H, m, C3′,5′-O—CH₂ —C₁₇H₃₅),3.68 (2H, t, J=6.6 Hz, C4′-O—CH₂ —C₁₇H₃₅), 3.87 (3H, s, C4-OMe),3.90(2H, d, J=6.0 Hz, Cy-CH₂ —OAr), 3.95(1H, s, C4′-H), 6.41(1H, d,J=2.1 Hz, C3-H), 6.54(1H, dd, J=1.5, 8.7 Hz, C5-H), 7.81(1H, d, J=8.7Hz, C6-H), 10.35(1H, s, CHO)

(v)4-Methoxy-2-(3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy)benzaldehyde(73.56 g, 69.8 mmol) was dissolved in THF-methanol (1100 ml+55 ml), andsodium borohydride (3.17 g, 83.8 mmol) was added at 0° C. After stirringthe mixture at room temperature for 1.5 hr, 0.2N hydrochloric acid (150ml) was added at 0° C. to quench the reaction. The solvent wasevaporated to about half, and the residue was dissolved in chloroform(1400 ml), washed twice with 0.1N hydrochloric acid (700 ml), and twicewith pure water (700 ml). The solvent was evaporated, and the residuewas precipitated with methanol (800 ml), and washed with acetonitrile(800 ml) to give4-methoxy-2-(3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy)benzylalcohol (71.5 g, 67.7 mmol, 92% vs methyl3,4,5-tris(octadecyloxy)cyclohexylcarboxylate).

¹H-NMR (300 MHz, CDCl₃): δ0.88(9H, t, J=6.9 Hz, C₁₇H₃₄-Me),1.15-1.45(101H, br, m, C1′-H, C2′,6′-H₂ , C3′,4′,5′-OCH₂—C₁₆ H₃₂ —CH₃),2.10(1H, t, J=6.3 Hz, OH), 3.18(2H, br, d, J=10.2 Hz, C3′,5′-H),3.37-3.57(4H, m, C3′,5′-O—CH₂ —C₁₇H₃₅), 3.68(2H, t, J=6.6 Hz, C4′-O—CH₂—C₁₇H₃₅), 3.80(3H, s, C4-Me), 3.86(2H, d, J=5.7 Hz, Cy-CH₂ —OAr),3.94(1H, s, C4′-H), 4.62(2H, d, J=6.3 Hz, Ar—CH₂ —OH), 6.39-6.49(2H, m,C3-H, C5-H), 7.17(1H, d, J=8.4 Hz, C6-H)

Example 11 Synthesis of2-methoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzylalcohol

(i) 3,4,5-Tris(octadecyloxy)cyclohexylmethyl alcohol (238 mg, 0.26mmol), 4-hydroxy-2-methoxybenzaldehyde (79 mg, 0.52 mmol) andtriphenylphosphine (149 mg, 0.57 mmol) were dissolved in THF (6 ml),diisopropyl azodicarboxylate (115 mg, 0.57 mmol) was added, and themixture was stirred for 5.5 hr. Water (1 ml) was added to the reactionmixture and the mixture was concentrated. The residue was precipitatedwith acetonitrile (2.5 ml) to give2-methoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzaldehyde(272 mg, 0.26 mmol, 100%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(9H, t, J=6.9 Hz, C₁₇H₃₄-Me),1.15-1.90(101H, br, m, C1′-H, C2′,6′-H₂ , C3′,4′,5′—OCH₂—C₁₆ H₃₂ —CH₃),3.18(2H, d, J=10.2 Hz, C3′,5′-H), 3.35-3.55(4H, m, C3′,5′-O—CH₂—C₁₇H₃₅), 3.68 (2H, t, J=6.7 Hz, C4′-O—CH₂ —C₁₇H₃₅), 3.75-4.00 (3H, m,Cy-CH₂ —OAr, C4′-H), 3.90(3H, s, C4-OMe), 6.42(1H, d, J=1.6 Hz, C3-H),6.51(1H, d, J=8.7 Hz, C5-H), 7.79(1H, d, J=8.6 Hz, C6-H), 10.28(1H, s,CHO)

(ii)2-Methoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzaldehyde(272 mg, 0.26 mmol) was suspended in chloroform-methanol (6 ml+0.5 ml),and sodium borohydride (29 mg, 0.77 mmol) was added. After stirring at60° C. overnight, the mixture was dissolved in chloroform (12 ml), andwashed with 0.5N hydrochloric acid (8 ml) and pure water (8 ml). Thesolvent was evaporated, and the residue was precipitated withacetonitrile (2.5 ml) to give2-methoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzylalcohol (260 mg, 0.25 mmol, 95%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(9H, t, J=6.9 Hz, C₁₇H₃₄-Me),1.15-1.45(101H, br, m, C1′-H, C2′,6′-H ₂, C3′,4′,5′-OCH₂—C₁₆ H₃₂ —CH₃),2.11(1H, t, J=5.9 Hz, OH), 3.18(2H, br, d, J=10.3 Hz, C3′,5′-H),3.35-3.57(4H, m, C3′,5′-O—CH₂ —C₁₇H₃₅), 3.68(2H, t, J=6.7 Hz, C4′-O—CH₂—C₁₇H₃₅), 3.75-3.90(2H, m, Cy-CH₂ —OAr), 3.84(3H, s, C4-OMe), 3.93 (1H,s, C4′-H), 4.60(2H, d, J=5.5 Hz, Ar—CH₂ —OH), 6.38-6.50(2H, m, C3-H,C5-H), 7.13(1H, d, J=8.2 Hz, C6-H)

Example 12 Synthesis of3,5-dimethoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzylalcohol

(i) 3,4,5-Tris(octadecyloxy)cyclohexylmethyltosylate (103 mg, 0.10mmol), 4-hydroxy-3,5-dimethoxybenzaldehyde (28 mg, 0.15 mmol) andpotassium carbonate (32 mg, 0.23 mmol) were suspended in DMF (1 ml), andthe suspension was stirred at 80° C. overnight. The reaction mixture wasdissolved in chloroform (5 ml), washed twice with 0.5N hydrochloric acid(3 ml), once with 5% aqueous sodium hydrogen carbonate solution (3 ml),and once with pure water (3 ml). The solvent was evaporated, and theresidue was precipitated with methanol (10 ml) to give4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]-3,5-dimethoxybenzaldehyde(73 mg, 0.07 mmol, yield 70%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(9H, t, J=6.6 Hz), 1.15-1.80(99H, br, m),3.18-3.21(2H, m), 3.43-3.49(4H, m), 3.69(2H, t, J=6.7 Hz), 3.78-3.87(9H,m), 6.05(2H, s), 10.34(1H, s)

(ii)4-[3′,4′,5′-Tris(octadecyloxy)cyclohexylmethyloxy]-3,5-dimethoxybenzaldehyde(73 mg, 0.07 mmol) was dissolved in THF (2 ml), 4 equivalents of sodiumborohydride was added, and the mixture was stirred at 40° C. for 3 hr.The solvent was evaporated, and chloroform was added. The mixture waswashed io successively with 1N hydrochloric acid, aqueous sodiumhydrogen carbonate solution and saturated brine. The solvent of theorganic layer was evaporated, and acetonitrile was added. Theprecipitate was collected by filtration and dried to give3,5-dimethoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzylalcohol (70 mg, 0.06 mmol).

¹H-NMR (300 MHz, CDCl₃):δ0.88(9H, t, J=6.6 Hz), 1.15-1.80(99H, br, m),3.18-3.21(2H, m), 3.43-3.50(4H, m), 3.69(2H, t, J=6.7 Hz), 3.78-3.87(9H,m), 4.69(2H, m), 6.03(2H, s)

Example 13 Synthesis of N-(4-hydroxymethyl-3-methoxyphenyl)3,4,5-tris(octadecyloxy)cyclohexylcarboxamide

(i) Methyl 4-amino-2-methoxybenzoate (79 mg, 0.44 mmol) was dissolved inchloroform (1 ml), and HOBt (7 mg, 0.05 mmol) and3,4,5-tris(octadecyloxy)cyclohexylcarboxylic acid (201 mg, 0.22 mmol)were added. EDC.HCl (45 mg, 0.23 mmol) was added under ice-cooling, andthe mixture was stirred at room temperature overnight. After completionof the reaction, the solvent was evaporated, and the residue wasprecipitated with acetonitrile (10 ml), and then purified by silica gelcolumn chromatography (chloroform/ethyl acetate=10:1) to giveN-(3-methoxy-4-methoxycarbonylphenyl)3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (70 mg, 0.06 mmol, yield27%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(9H, t, J=6.6 Hz), 1.15-1.80(99H, m),3.19-3.22(2H, m), 3.39-3.49(4H, m), 3.69(2H, t, J=6.7 Hz), 3.7(1H, br,s), 3.83(3H, s), 3.92(3H, s), 6.82(1H, d, J=6.0 Hz), 7.36(1H, s),7.63(1H, s), 7.81(1H, d, J=6.0 Hz)

(ii) N-(3-Methoxy-4-methoxycarbonylphenyl)3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (70 mg, 0.06 mmol) wasdissolved in dehydrated THF (1 ml), 1M DIBAL/toluene (0.2 ml, 0.012mmol) was added dropwise, and the mixture was stirred for 5 hr. Aftercompletion of the reaction, 1N hydrochloric acid was added to quench thereaction, and the mixture was extracted with chloroform (5 ml) andwashed with 1N hydrochloric acid (3 ml). The solvent was evaporated andthe residue was precipitated with methanol (10 ml) and slurry-washedwith acetonitrile (5 ml) and 1N hydrochloric acid (5 ml) to giveN-(4-hydroxymethyl-3-methoxyphenyl)3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (60 mg, 0.06 mmol, yield100%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(9H, t, J=6.6 Hz), 1.15-1.80 (99H, m),3.19-3.22(2H, m), 3.39-3.49(4H, m), 3.69(2H, t, J=6.7 Hz), 3.88-3.92(4H,m), 4.63(2H, s), 6.77(1H, d, J=6.0 Hz), 7.18(1H, d, J=6.0 Hz), 7.51(1H,s), 7.61(1H, s)

Example 14 Synthesis of N-(5-hydroxymethyl-2-methoxyphenyl)3,4,5-tris(octadecyloxy)cyclohexylcarboxamide

(i) Methyl 3-amino-4-methoxybenzoate (81 mg, 0.44 mmol) was dissolved inchloroform (1 ml), HOBt (7 mg, 0.05 mmol) and3,4,5-tris(octadecyloxy)cyclohexylcarboxylic acid (199 mg, 0.22 mmol)were added. EDC.HCl (45 mg, 0.23 mmol) was added under ice-cooling, andthe mixture was stirred at room temperature overnight. After completionof the reaction, the solvent was evaporated, and the residue wasprecipitated with acetonitrile (10 ml) to giveN-(2-methoxy-5-methoxycarbonylphenyl)3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (225 mg, 0.21 mmol, yield95%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(9H, t, J=6.6 Hz), 1.15-1.80(99H, m),3.19-3.22(2H, m), 3.39-3.49(4H, m), 3.69(2H, t, J=6.7 Hz), 3.73(1H, br,s), 3.88(3H, s), 3.94(3H, s), 6.91(1H, d, J=6.0 Hz), 7.79-86(2H, m),7.63(1H, s)

(ii) N-(2-Methoxy-5-methoxycarbonylphenyl)3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (225 mg, 0.21 mmol) wasdissolved in dehydrated THF (2.5 ml), 1M DIBAL/toluene (0.6 ml, 0.6 eq)was added dropwise, and the mixture was stirred for 5 hr. Aftercompletion of the reaction, 1N hydrochloric acid was added to quench thereaction, and the mixture was extracted with chloroform (10 ml), andwashed with 1N hydrochloric acid (5 ml). The solvent was evaporated andthe residue was precipitated with methanol (15 ml) and slurry-washedwith acetonitrile (10 ml) and 1N hydrochloric acid (10 ml) to giveN-(5-hydroxymethyl-2-methoxyphenyl)3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (200 mg, 0.18 mmol, yield86%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(9H, t, J=6.6 Hz), 1.15-1.80(99H, m),3.19-3.22(2H, m), 3.39-3.49(4H, m), 3.69(2H, t, J=6.7 Hz), 3.83-3.94(4H,m), 4.59(2H, m), 6.86(1H, d, J=6.0 Hz), 7.07(1H, d, J=6.0 Hz), 7.90(1H,s), 8.37(1H, s)

Example 15 Synthesis of N-(4-hydroxymethylphenyl)3,4,5-tris(octadecyloxy)cyclohexylcarboxamide

4-Aminobenzyl alcohol (282 mg, 2.29 mmol) was dissolved in chloroform(40 ml), and HOBt (32 mg, 0.23 mmol) and3,4,5-tris(octadecyloxy)cyclohexylcarboxylic acid (1.11 g, 1.19 mmol)were added. EDC.HCl (356 mg, 1.86 mmol) and pure water (120 μl) wereadded under ice-cooling, and the mixture was stirred at room temperatureovernight. After completion of the reaction, the solvent was evaporated,and the residue was precipitated with acetonitrile (10 ml), and isolatedby silica gel column chromatography (chloroform/ethyl acetate=10:1) togive N-(4-hydroxymethylphenyl)3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (556 mg, 0.54 mmol, yield45%).

¹H-NMR (300 MHz, CDCl₃): δ0.87(9H, t, J=6.6 Hz), 1.12-1.83(99H, m),3.20-3.24(2H, m), 3.38-3.45(4H, m), 3.69(2H, t, J=6.7 Hz), 3.88-3.92(1H,m), 4.63(2H, s), 7.27(2H, d, J=6.0 Hz), 7.59(2H, d, J=6.0 Hz), 8.01(1H,s)

Example 16 Condensation of4-(12′-docosyloxy-1′-dodecyloxy)-2-methoxybenzyl alcohol withFmoc-Cys(Trt)-OH

4-(12′-Docosyloxy-1′-dodecyloxy)-2-methoxybenzyl alcohol (300 mg, 0.46mmol), Fmoc-Cys(Trt)-OH (326 mg, 0.56 mmol) and DMAP (11 mg, 0.090 mmol)were dissolved in chloroform (6 ml), EDC.HCl (116 mg, 0.61 mmol) wasadded at 0° C., and the mixture was stirred at room temperature for 2.5hr. The solvent was evaporated, and the residue was precipitated withmethanol to give a condensed product (586 mg, 0.48 mmol, 100%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(3H, t, J=6.8 Hz, —OC₂₁H₄₂-Me),1.15-1.65(58H, br, Alkyl-H), 1.76(2H, m, Ar—OCH₂—CH₂ —), 2.50-2.70(2H,m, S—CH₂ —), 3.39 (4H, t, J=6.7 Hz, —C₁₁H₂₂—CH₂ —O—CH₂ —C₂₁H₄₃), 3.71(3H, s, OMe), 3.91(2H, t, J=6.2 Hz, Ar—O—CH₂ —), 4.15-4.25(1H, m,fluorene C9-H), 4.25-4.40(3H, m, fluorene-CH₂ —O—, Cys α-H), 5.13(2H, d,J=2.9 Hz, benzyl-H), 5.27(1H, d, J=8.3 Hz, Fmoc-NH—), 6.35-6.45(2H, m,Ph C3,5-H), 7.10-7.45(21H, m, C2,6-H, fluorene C2,3,6,7-H, Trt),7.59(2H, d, J=7.4 Hz, fluorene C1,8-H), 7.76(2H, d, J=7.0 Hz, fluoreneC4,5-H)

Example 17 Condensation of2-(12′-docosyloxy-1′-dodecyloxy)-4-methoxybenzyl alcohol withFmoc-Cys(Trt)-OH

The title compound was synthesized from2-(12′-docosyloxy-1′-dodecyloxy)-4-methoxybenzyl alcohol in the samemanner as described in Example 16.

¹H-NMR (300 MHz, CDCl₃): δ0.88(3H, t, J=6.9 Hz, —OC₂₁H₄₂-Me),1.15-1.65(58H, br, Alkyl-H), 1.76(2H, m, Ar—O—CH₂—CH₂ —), 2.50-2.70(2H,m, S—CH₂ —), 3.38 (4H, t, J=6.7 Hz, —C₁₁H₂₂—CH₂ —O—CH₂ —C₂₁H₄₃),3.78(3H, s, OMe), 3.86(2H, t, J=6.5 Hz, Ar—O—CH₂ —), 4.15-4.25(1H, m,fluorene C9-H), 4.25-4.35(3H, m, fluorene-CH₂ —O—, Cys α-H), 5.16(2H, s,benzyl-H), 5.28(1H, d, J=8.1 Hz, Fmoc-NH—), 6.35-6.43(2H, m, Ph C3,5-H),7.10-7.45(21H, m, C2,6-H, fluorene C2,3,6,7-H, Trt), 7.59(2H, d, J=7.6Hz, fluorene C1,8-H), 7.76(2H, d, J=6.9 Hz, fluorene C4,5-H)

Example 18 Condensation of 4-(12′-docosyloxy-1′-dodecyloxy)benzylalcohol with Fmoc-Cys(Trt)-OH

The title compound was synthesized from4-(12′-docosyloxy-1′-dodecyloxy)benzyl alcohol in the same manner asdescribed in Example 16.

¹H-NMR (300 MHz, CDCl₃): δ0.88(3H, t, J=6.9 Hz, —OC₂₁H₄₂-Me),1.15-1.65(58H, br, Alkyl-H), 1.76(2H, m, Ar—O—CH₂—CH₂ —), 2.50-2.70(2H,m, S—CH₂ —), 3.39 (4H, t, J=6.6 Hz, —C₁₁H₂₂—CH₂ —O—CH₂ —C₂₁H₄₃),3.90(2H, t, J=6.2 Hz, Ar—O—CH₂ —), 4.15-4.25(1H, m, fluorene C9-H),4.25-4.35(3H, m, fluorene-CH₂ —O—, Cys α-H), 5.08 (2H, s, benzyl-H),5.26(1H, d, J=8.3 Hz, Fmoc-NH—), 6.82(2H, d, J=8.4 Hz, Ph, C3,5-H),7.15-7.45(21H, m, C2,6-H, fluorene C2,3,6,7-H, Trt), 7.59(2H, d, J=7.5Hz, fluorene C1,8-H), 7.76(2H, d, J=7.4 Hz, fluorene C4,5-H)

Example 19 Condensation of4-methoxy-2-(3′,4′,5′-tris(octadecyloxy)benzyloxy)benzyl alcohol withFmoc-Cys(Trt)-OH

The title compound was synthesized from4-methoxy-2-(3′,4′,5′-tris(octadecyloxy)benzyloxy)benzyl alcohol in thesame manner as described in Example 16.

¹H-NMR (300 MHz, CDCl₃): δ0.88 (9H, t, J=6.9 Hz, OC₁₈H₃₇C18-H),1.10-1.60(90H, br, OC₁₈H₃₇C3-17-H), 1.75(6H, m, OC₁₈H₃₇C2-H),2.54-2.68(2H, m, Trt-S—CH₂—), 3.75(3H, s, -Bzl-OMe), 3.92(6H, m,OC₁₈H₃₇C1-H), 4.19(1H, m, fluorene C9-H), 4.26-4.38(3H, m, fluorene-CH₂—, Cys α-H), 4.88 (2H, s, Ar₁—CH₂ —O—Ar₂), 5.16-5.28(3H, m, NH, CysO—CH₂—Ar₁), 6.42-6.45(2H, m, Ph C3,5-H), 6.57(2H, s, Ph C2′,6′-H),7.10-7.45(20H, m, Ph C6-H, Trt, fluorene C2,3,6,7-H), 7.57(1H, d, J=7.2Hz, fluorene C1,8-H), 7.75(2H, d, J=7.2 Hz, fluorene C4,5-H)

Example 20 Condensation of 2-docosyloxy-4-methoxybenzyl alcohol withFmoc-Met-OH

2-Docosyloxy-4-methoxybenzyl alcohol (213 mg, 0.46 mmol) was dissolvedin chloroform (3 ml), and Fmoc-Met-OH (188 mg, 0.51 mmol) and DMAP (6mg, 0.05 mmol) were added. EDC HCl (107 mg, 0.56 mmol) was added underice-cooling, and the mixture was stirred at room temperature for 1 hr.After completion of the reaction, the solvent was evaporated, and theresidue was precipitated with acetonitrile (10 ml) to give a condensedproduct (349 mg, 0.43 mmol, yield 93%).

¹H-NMR (300 MHz, CDCl₃): δ0.88(3H, t, J=6.8 Hz), 1.21-1.79(40H, m),1.96-2.16(5H, m), 2.43-2.48(2H, m), 3.78(3H, s), 3.93(2H, t, J=6.3 Hz),4.21(1H, t, J=3.7 Hz), 4.38-4.51(3H, m), 5.12-5.24(2H, m), 6.41-6.43(2H,m), 7.21(1H, d, J=8.8 Hz), 7.28-7.42(4H, m), 7.59(2H, d, J=7.3 Hz),7.76(2H, d, J=7.3 Hz)

Example 21 Condensation of4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzylalcohol with Fmoc-Met-OH

The title compound was synthesized from4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzylalcohol in the same manner as described in Example 20.

¹H-NMR (300 MHz, CDCl₃): δ0.88(9H, t, J=6.8 Hz), 1.21-1.81(96H, m),1.95-2.16(5H, m), 2.45-2.46(2H, m), 3.64-3.68(2H, m), 3.77(2H, t, J=6.3Hz), 4.17(1H, t, J=3.7 Hz), 4.37-4.48(3H, m), 5.12-5.23(2H, m),6.39-6.42(2H, m), 7.23(1H, d, J=8.8 Hz), 7.29-7.42(4H, m), 7.59(2H, d,J=7.3 Hz), 7.75(2H, d, J=7.3 Hz)

Example 22 Condensation of 2-docosyloxy-4-methoxybenzyl alcohol withFmoc-Trp(Boc)-OH

2-Docosyloxy-4-methoxybenzyl alcohol (200 mg, 0.43 mmol) was dissolvedin chloroform (3 ml), and Fmoc-Trp(Boc)-OH (250 mg, 0.47 mmol) and DMAP(6 mg, 0.05 mmol) were added. EDC.HCl (108 mg, 0.56 mmol) was addedunder ice-cooling, and the mixture was stirred at room temperature for2.5 hr. After completion of the reaction, the solvent was evaporated,and the residue was precipitated with acetonitrile (10 ml) to give acondensed product (355 mg, 0.37 mmol, yield 85%).

¹H-NMR (300 MHz, CDCl₃): δ0.86(3H, t, J=6.8 Hz), 1.22-1.77(49H, m),3.21-3.28(2H, m), 3.79(3H, s), 3.91(2H, t, J=6.3 Hz), 4.18(1H, t, J=3.7Hz), 4.28-4.37(3H, m), 4.76-4.79(1H, m), 5.07-5.21(2H, m), 6.38-6.41(2H,m), 7.20(1H, d, J=8.8 Hz), 7.27-7.55(11H, m), 7.75(2H, d, J=7.3 Hz),8.10(1H, m)

Example 23 Condensation of4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzylalcohol with Fmoc-Trp(Boc)-OH

The title compound was synthesized from4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzylalcohol in the same manner as described in Example 22.

¹H-NMR (300 MHz, CDCl₃): δ0.88(9H, t, J=6.8 Hz), 1.20-1.76(105H, m),3.24-3.28(2H, m), 3.63-3.67(6H, m), 3.78(3H, s), 4.16(1H, t, J=3.7 Hz),4.32-4.35(3H, m), 4.74-4.76(1H, m), 5.09-5.20(2H, m), 6.37-6.39(2H, m),7.18(1H, d, J=8.8 Hz), 7.26-7.52(11H, m), 7.74(2H, d, J=7.3 Hz),8.09(1H, m)

Comparative Example 1 Condensation of 3,4,5-tris(actadecyloxy)benzylalcohol with Fmoc-Cys(Trt)-OH

The title compound was synthesized from 3,4,5-tris(octadecyloxy)benzylalcohol in the same manner as described in Example 16.

¹H-NMR (300 MHz, CDCl₃): δ0.88(9H, t, J=6.9 Hz, —C₁₇H₃₄-Me),1.00-1.60(90H, alkyl-H), 1.65-1.80(6H, br, —O—CH₂—CH₂ —C₁₆H₃₃),2.50-2.75(2H, br, Trt-S—CH₂ —), 3.90(6H, br, s, —O—CH₂ —C₁₇H₃₅),4.21(1H, t, J=6.2 Hz, fluorene C9-H), 4.25-4.45(3H, br, fluorene-CH₂ —,Cys α-H), 5.04(2H, s, benzyl-H), 5.26(1H, d, J=8.4 Hz, N—H), 6.50(2H, s,Ph C2,6-H), 7.10-7.45(13H, m, Trt, fluorene C3,4,5,6-H), 7.59(2H, d,J=6.8 Hz, fluorene C1,8-H), 7.76(2H, d, J=6.9 Hz, fluorene C4,5-H)

Comparative Example 2 Condensation of 2,4-di(docosyloxy)benzyl alcoholwith Fmoc-Cys(Trt)-OH

The title compound was synthesized from 2,4-di(docosyloxy)benzyl alcoholin the same manner as described in Example 16.

¹H-NMR (300 MHz, CDCl₃): δ0.88(6H, t, J=6.9 Hz, OC₂₂H₄₅C22-H),1.10-1.60(76H, br, OC₂₂H₄₅C3-21-H), 1.73(4H, m, OC₂₂H₄₅C2-H) 2.63 (2H,m, Trt-S—CH₂ —), 3.88 (4H, m, OC₂₂H₄₅C1-H), 4.22 (1H, t, J=6.8 Hz,fluorene C9-H), 4.27-4.35(3H, m, fluorene-CH₂ —, Cys α-H), 5.15(2H, s,CysO—CH₂ —Ar₁), 5.27(1H, d, J=8.0 Hz, NH), 6.37-6.39(2H, m, Ph C3,5-H),7.10-7.41(20H, m, Ph C6-H, Trt, fluorene C2,3,6,7-H), 7.59(2H, d, J=7.2Hz, fluorene C1,8-H), 7.75(2H, d, J=7.2 Hz, fluorene C4,5-H)

Comparative Example 3 Condensation of 3,4,5-tris(octadecyloxy)benzylalcohol with Fmoc-Met-OH

The title compound was synthesized from 3,4,5-tris(octadecyloxy)benzylalcohol in the same manner as described in Example 20.

¹H-NMR (300 MHz, CDCl₃): δ0.87(9H, t, J=6.8 Hz), 1.44-1.79(105H, m),3.20-3.28(2H, m), 3.89-3.91(6H, m), 4.21(1H, m), 4.36(2H, d, J=6.0 Hz),4.78-5.09(3H, m), 6.46(2H, d, J=6.0 Hz), 7.18-7.55(11H, m), 7.75(2H, d,J=6.0 Hz), 8.11(1H, m)

Comparative Example 4 Condensation of 3,4,5-tris(octadecyloxy)benzylalcohol and Fmoc-Trp(Boc)-OH

The title compound was synthesized from 3,4,5-tris(octadecyloxy)benzylalcohol in the same manner as described in Example 22.

¹H-NMR(300 MHz, CDCl₃): δ0.87(9H, t, J=6.8 Hz), 1.21-1.84(96H, m),2.00-2.04(5H, m), 2.48(2H, m), 3.92-3.96(6H, m), 4.19-4.24(1H, m),4.40(d, 2H, J=6.0 Hz), 4.53-4.55(1H, m), 5.08(2H, m), 6.52(s, 2H),7.27(2H, d, J=6.0 Hz), 7.38(2H, d, J=6.0 Hz), 7.58(2H, d, J=6.0 Hz),7.76(2H, d, J=6.0 Hz)

Example 24 Introduction of Fmoc-Leu-OH into benzyl alcohol compound(anchor)

4-(12′-Docosyloxy-1′-dodecyloxy)-2-methoxybenzyl alcohol (hereinafter tobe sometimes referred to as Bzl (2-MeO-4-OC₁₂OC₂₂)—OH, 651 mg, 1.01mmol) was dissolved in chloroform (7 mL), Fmoc-Leu-OH (711 mg, 2.01mmol) and dimethylaminopyridine (24.6 mg, 201 μmol) were added at roomtemperature, and EDC HCl (424 mg, 2.21 mmol) was added in an ice bath.The mixture was warmed to room temperature, and stirred overnight. Thereaction mixture was concentrated under reduced pressure, methanol wasadded to the residue, and the precipitated crystals were collected byfiltration to give Fmoc-Leu-OBzl (2-MeO-4-OC₁₂OC₂₂) (942 mg, 95% yieldrelative to Bzl (2-MeO-4-OC₁₂OC₂₂)—OH).

¹H-NMR (300 MHz, CDCl₃): δ0.80-1.00(9H, m, —CO₂₁H₄₂-Me, LeuMe),1.15-1.85(61H, br, Alkyl-H, Leu-CH₂ —CHMe₂), 3.39(4H, t, J=6.7 Hz,—C₁₁H₂₂—CH₂ —O—CH₂ —C₂₁H₄₃), 3.78 (3H, s, OMe), 3.92 (2H, t, J=6.5 Hz,Ar—O—CH₂ —), 4.15-4.25(1H, m, fluorene C9-H), 4.30-4.50(3H, m,fluorene-CH₂ —O—, Leu α-H), 5.05-5.25(3H, m, benzyl-H, Fmoc-NH—),6.35-6.45(2H, m, Ph C3,5-H), 7.19(1H, d, J=8.7 Hz, Ph C6-H), 7.31(2H, d,J=7.4 Hz, fluorene C2,7-H), 7.40(2H, t, J=7.3 Hz, fluorene C3,6-H),7.59(2H, d, J=7.3 Hz, fluorene C1,8-H), 7.76(2H, d, J=7.4 Hz, fluoreneC4,5-H)

Example 25 Removal of Fmoc group from Fmoc-Leu-OBzl (2-MeO-4-OC₁₂OC₂₂),followed by condensation with Fmoc-Leu-OH

(i) The crude crystals (942 mg) of Fmoc-Leu-OBzl (2-MeO-4-OC₁₂OC₂₂) weredissolved in chloroform (9 mL), and diethylamine (1.99 mL, 19.2 mmol)was added dropwise under ice-cooling. The mixture was warmed to roomtemperature, acetonitrile (4.5 mL) was added, and the mixture wasstirred for 3.5 hr. The reaction mixture was concentrated under reducedpressure, and the residue was precipitated with acetonitrile (10 mL) togive Leu-OBzl (2-MeO-4-OC₁₂OC₂₂) as wet crystals.

¹H-NMR (300 MHz, CDCl₃): δ0.80-1.00(9H, m, —CO₂₁H₄₂-Me, Leu Me),1.15-1.85(61H, br, Alkyl-H, Leu-CH₂ —CHMe₂), 3.39(4H, t, J=6.7 Hz,—C₁₁H₂₂—CH₂ —0—CH₂ —C₂₁H₄₃), 3.46(1H, dd, J=5.9,8.4 Hz, Leu α-H),3.81(3H, s, OMe), 3.95(2H, t, J=6.5 Hz, Ar—O—CH₂ —), 5.11(2H, s,benzyl-H), 6.40-6.50(2H, m, Ph C3,5-H), 7.20(1H, d, J=8.6 Hz, Ph C6-H)

(ii) The obtained wet crystals of Leu-OBzl (2-MeO-4-OC₁₂OC₂₂) weredissolved in chloroform (13 mL), Fmoc-Leu-OH (373 mg, 1.06 mmol) andHOBt (14.3 mg, 106 μmol) were added at room 30 temperature, and EDC.HCl(223 mg, 1.16 mmol) was further added under ice-cooling. The mixture waswarmed to room temperature, stirred overnight, and concentrated underreduced pressure. Methanol (10 mL) was added to the residue, and theprecipitate was collected by filtration to give Fmoc-Leu-Leu-OBzl(2-MeO-4-OC₁₂OC₂₂) (1.02 g, 93% yield relative to Bzl(2-MeO-4-OC₁₂OC₂₂)OH).

¹H-NMR (300 MHz, CDCl₃): δ0.80-1.00(15H, m, —OC₂₁H₄₂-Me, Leu Me),1.15-1.85(64H, br, Alkyl-H, Leu —CH₂ —CHMe₂), 3.39(4H, t, J=6.7 Hz,—C₁₁H₂₂—CH₂ —O—CH₂ —H₂₁H₄₃), 3.79 (3H, s, OMe), 3.94 (2H, t, J=6.3 Hz,Ar—O—CH₂ —), 4.10-4.30(2H, m, fluorene C9-H, Leu α-H), 4.39(2H, d, J=7.1Hz, fluorene-CH₂ —O—), 4.55-4.70(1H, br, Leu α-H), 5.00-5.30(3H, m,benzyl-H, —NH—), 6.20-6.30(1H, br, —NH—), 6.40-6.50(2H, m, Ph C3,5-H),7.17(1H, d, J=7.9 Hz, Ph C6-H), 7.32(2H, d, J=7.4 Hz, fluorene C2,7-H),7.40(2H, t, J=7.4 Hz, fluorene C3,6-H), 7.58(2H, d, J=7.2 Hz, fluoreneC1,8-H), 7.76(2H, d, J=7.4 Hz, fluorene C4,5-H)

Example 26 Removal of Fmoc group from Fmoc-Leu-Leu-OBzl(2-MeO-4-OC₁₂OC₂₂), followed by condensation with Fmoc-D-Lys(Boc)-OH

(i) Fmoc-Leu-Leu-OBzl (2-MeO-4-OC₁₂OC₂₂) (1.02 g) was dissolved inchloroform (10 mL), and diethylamine (1.94 mL, 18.7 mmol) was addeddropwise under ice-cooling. The mixture was warmed to room temperature,acetonitrile (5 mL) was added, and the mixture was stirred for 2.5 hr.Diethylamine (970 μL, 9.35 mmol) was added, and the mixture was furtherstirred for 1 hr. The reaction mixture was concentrated under reducedpressure, and the residue was precipitated with acetonitrile (10 mL) togive Leu-Leu-OBzl (2-MeO-4-OC₁₂OC₂₂) as wet crystals.

¹H-NMR (300 MHz, CDCl₃): δ0.80-1.00(15H, m, —OC₂₁H₄₂-Me, Leu Me),1.15-1.85(70H, br, Alkyl-H, Leu-CH₂ —CHMe₂), 3.39(4H, t, J=6.7 Hz,—C₁₁H₂₂—CH₂ —O—CH₂ —C₂₁H₄₃), 3.46(1H, dd, J=5.9, 8.4 Hz, Leu α-H),3.81(3H, s, OMe), 3.95(2H, t, J=6.5 Hz, Ar—O—CH₂ —), 5.11(2H, s,benzyl-H), 6.40-6.50(2H, m, Ph C3,5-H), 7.20(1H, d, J=8.6 Hz, Ph C6-H),7.59(1H, d, J=8.5 Hz, N—H)

(ii) The obtained wet crystals of Leu-Leu-OBzl (2-MeO-4-OC₁₂OC₂₂) weredissolved in chloroform (13 mL), Fmoc-D-Lys(Boc)-OH (481 mg, 1.03 mmol)and HOBt (13.9 mg, 103 μmol) were added at room temperature, and EDC HCl(216 mg, 1.13 mmol) was further added under ice-cooling. The mixture waswarmed to room temperature, stirred overnight and concentrated underreduced pressure. The residue was precipitated with methanol (10 mL) togive Fmoc-D-Lys(Boc)-Leu-Leu-OBzl (2-MeO-4-OC₁₂OC₂₂) (1.14 g, 86% yieldrelative to Bzl (2-MeO-4-OC₁₂OC₂₂)OH).

¹H-NMR (300 MHz, CDCl₃): δ0.80-1.00(15H, m, —OC₂₁H₄₂-Me, Leu Me),1.15-1.85(79H, br, Alkyl-H, Leu —CH₂ —CHMe₂, Lys Boc-NH—CH₂—(CH₂ ) ₃ —),3.05-3.20(2H, br, Boc-NH—CH₂ —), 3.39(4H, t, J=6.7 Hz, —C₁₁H₂₂CH₂ —O—CH₂—C₂₁H₄₃), 3.77 (3H, s, OMe), 3.93(2H, t, J=6.5 Hz, Ar—O—CH₂ —),4.05-4.15(1H, br, —NH—CHR—CO—), 4.15-4.25(1H, m, fluorene C9-H),4.35-4.50(3H, br, fluorene-CH₂ —, —NH—CHR—CO— or —NH—), 4.50-4.70(2H,br, —NH—CHR—CO— or —NH—), 5.09(2H, q, J=12.0 Hz, benzyl-H),5.45-5.55(1H, br, —NH—), 6.35-6.55(4H, m, Ph C3,5-H, —NH—), 7.16(1H, d,J=7.9 Hz, Ph C6-H), 7.32(2H, d, J=7.3 Hz, fluorene C2,7-H), 7.40(2H, t,J=7.3 Hz, fluorene C3,6-H), 7.59(2H, d, J=7.1 Hz, fluorene C1,8-H),7.76(2H, d, J=7.4 Hz, fluorene C4,5-H)

Example 27 Removal of Fmoc group from Fmoc-D-Lys(Boc)-Leu-Leu-OBzl(2-MeO-4-OC₁₂OC₂₂), followed by condensation with Fmoc-D-Lys(Boc)-OH

(i) Fmoc-D-Lys(Boc)-Leu-Leu-OBzl(2-MeO-4-OC₁₂OC₂₂) (1.14 g) wasdissolved in chloroform (12 mL), and diethylamine (2.68 mL, 25.8 mmol)was added dropwise under ice-cooling. The mixture was warmed to roomtemperature, acetonitrile (4 mL) was added, and the mixture was stirredfor 2 hr. Diethylamine (890 μL, 8.58 mmol) was added, and the mixturewas further stirred for 0.5 hr. The reaction mixture was concentratedunder reduced pressure, and the residue was precipitated withacetonitrile (10 mL) to give D-Lys(Boc)-Leu-Leu-OBz1(2-MeO-4-OC₁₂OC₂₂)as wet crystals.

¹H-NMR (300 MHz, CDCl₃): δ0.80-1.00(15H, m, —OC₂₁H₄₂-Me, Leu Me),1.15-1.85(79H, br, Alkyl-H, Leu —CH₂ —CHMe₂, Lys Boc-NH—CH²—(CH₂ ) ₃ ),3.11(2H, br, d, J=5.6 Hz, Boc—NH—CH₂ —), 3.39(5H, t, J=6.7 Hz,—C₁₁H₂₂—CH₂ —O—CH₂ —C₂₁H₄₃, —NH—CHR—CO—), 3.80 (3H, s, OMe), 3.95(3H, t,J=6.5 Hz, Ar—O—CH₂ —, —NH—CHR—CO—), 4.30-4.45(1H, br, —NH—CHR—CO—),4.50-4.70(2H, br, —NH₂ —), 5.08(1H, d, J=11.9 Hz, benzyl-H), 5.15(1H, d,J=11.9 Hz, benzyl-H), 6.35-6.50(3H, m, Ph C3,5-H, N—H), 6.57(1H, d,J=8.1 Hz, N—H), 7.18(1H, d, J=8.9 Hz, Ph C6-H), 7.64(1H, d, J=8.0 Hz)

(ii) The obtained wet crystals of D-Lys(Boc)-Leu-Leu-OBzl(2-MeO-4-OC₁₂OC₂₂) were dissolved in chloroform (15 mL),Fmoc-D-Lys(Boc)-OH (444 mg, 948 μmol) and HOBt (12.8 mg, 94.7 μmol) wereadded at room temperature, and EDC HCl (200 mg, 1.04 mmol) was furtheradded under ice-cooling. The mixture was warmed to room temperature andstirred overnight. Chloroform (20 mL), Fmoc-D-Lys(Boc)-OH (89 mg, 190μmol) and EDC.HCl (40 mg, 210 μmol) were added, and the mixture wasfurther stirred for 1 hr and concentrated under reduced pressure. Theresidue was precipitated with methanol (15 mL) to giveFmoc-D-Lys(Boc)-D-Lys(Boc)-Leu-Leu-OBzl (2-MeO-4-OC₁₂OC₂₂) (1.35 g, 85%yield relative to Bzl (2-MeO-4-OC₁₂OC₂₂)OH).

¹H-NMR (300 MHz, CDCl₃): 60.80-1.00(15H, m, —OC₂₁H₄₂-Me, Leu Me),1.15-2.00(94H, br, Alkyl-H, -Leu —CH₂ —CHMe₂, Lys Boc-NH—CH₂—(CH₂)₃ ),3.00-3.20(4H, br, Boc-NH—CH₂ —), 3.10-3.30(1H, m, —NH—CHR—CO—), 3.39(4H,t, J=6.7 Hz, —C₁₁H₂₂—CH₂ —O—CH₂ —C₂₁H₄₃), 3.77(3H, s, OMe), 3.93(2H, t,J=6.5 Hz, Ar—O—CH₂ —), 4.05-4.20(1H, br, —NH—CHR—CO—), 4.15-4.25(1H, m,fluorene C9-H), 4.30-4.50(3H, br, fluorene-CH₂ —, —NH—CHR—CO— or —NH—),4.50-4.75(2H, br, —NH—CHR—CO— or —NH—), 5.04(1H, d, J=11.9 Hz,benzyl-H), 5.14(1H, d, J=11.9 Hz, benzyl-H), 5.60-5.80(1H, br, —NH—),6.40-6.60(3H, m, Ph C3,5-H, —NH—), 6.70-6.80(1H, br, —NH—), 7.16(1H, d,J=8.2 Hz, Ph C6-H), 7.32(2H, d, J=7.2 Hz, fluorene C2,7-H), 7.39(2H, t,J=7.2 Hz, fluorene C3,6-H), 7.61(2H, t, J=5.6 Hz, fluorene C1,8-H),7.76(2H, d, fluorene C4,5-H)

Example 28 Removal of anchor fromFmoc-D-Lys(Boc)-D-Lys(Boc)-Leu-Leu-OBzl (2-MeO-4-OC₁₂OC₂₂)

The crude crystals (1.23 g) of Fmoc-D-Lys(Boc)-D-Lys(Boc)-Leu-Leu-OBzl(2-MeO-4-OC₁₂OC₂₂) were dissolved in a mixture of chloroform (12 mL) andheptane (12 mL), and 3% trifluoroacetic acid/(chloroform-heptane=1:1)solution was added dropwise under ice-cooling. The reaction mixture wasstirred in a water bath at 10-15° C. for 3 hr, and 2.5% aqueous sodiumhydrogen carbonate solution (18 mL) and chloroform (18 mL) were added.0.1N Hydrochloric acid was added, and the aqueous layer was adjusted topH 2. The aqueous layer was removed, and the organic layer was washed 3times with purified water (10 mL). The combined organic layers wereconcentrated under reduced pressure, and heptane (30 mL) was added tothe residue. The precipitated crystals were washed at 40° C. andcollected by filtration to give Fmoc-D-Lys(Boc)-D-Lys(Boc)-Leu-Leu-OH(800 mg, 93%).

MS(MH⁻)921.5

Example 29 Removal of anchor (concomitant with removal of Boc group)from Fmoc-D-Lys(Boc)-D-Lys(Boc)-Leu-Leu-OBzl (2-MeO-4-OC₁₂OC₂₂)

The crude crystals (100 mg) of Fmoc-D-Lys(Boc)-D-Lys(Boc)-Leu-Leu-OBzl(2-MeO-4-OC₁₂OC₂₂) were added to a solution (2 ml) of trifluoroaceticacid:triisopropylsilane:water=95:2.5:2.5 under ice-cooling, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas concentrated under reduced pressure, and methyl tert-butyl ether(MTBE)/cyclohexane was added to the residue. The precipitate was washedat 40° C. and collected by filtration to giveFmoc-D-Lys-D-Lys-Leu-Leu-OH (29 mg).

MS(MH⁺) 723.3

Experimental Example 1 Comparison of Anchor of the Present Invention andKnown Anchor in Yield of Deprotection Reaction of Anchor-Protected Formof Fmoc-Cys(Trt)-OH

Test Compounds

The compounds described in the aforementioned Examples 16, 17, 18 and19, wherein Fmoc-Cys(Trt)-OH was introduced into the four kinds ofanchors of the present invention, (hereinafter to be referred to asExample compounds 16, 17, 18 and 19) were used as test compounds.

In addition, Fmoc-Cys(Trt)-OBzl (3,4,5-tri-OC₁₈) obtained by introducingFmoc-Cys(Trt)-OH into the following formula:

which is the anchor molecule described in the aforementioned non-patentdocument 1 and patent document 1 (hereinafter to be referred to as Bzl(3,4,5-tri-OC₁₈)OH, and Fmoc-Cys(Trt)-OBzl (2,4-di-OC₂₂) obtained byintroducing Fmoc-Cys(Trt)-OH into the following formula:

which is the anchor molecule described in the aforementioned patentdocument 3 (hereinafter to be referred to as Bzl(2,4-di-OC₂₂)OH), thatis, the compounds described in the aforementioned Comparative Examples 1and 2, respectively, were used as test compounds (hereinafter to bereferred to as Comparative Example compounds 1 and 2).

Experiment Method

(i) To each test compound was added trifluoroacetic acid(TFA:H₂O:TIS=95:2.5:2.5) in triisopropylsilane-water at roomtemperature, and the mixture was stirred for 2 hr. The total yield ofthe anchor-deprotected forms, that is, Fmoc-Cys-OH and Fmoc-Cys(Trt)-OH,was measured and the yield was calculated (Table 1).

(ii) Each test compound was added to 2% trifluoroacetic acid-chloroformsolution at room temperature, and the mixture was stirred for 1 hr. Thetotal yield of the anchor-deprotected forms, that is, Fmoc-Cys-OH andFmoc-Cys(Trt)-OH, was measured, and the yield was calculated (Table 2).

Experiment Results

In both cases of the above-mentioned (i) and (ii), the starting materialdisappeared, and the deprotection reaction of Example compounds 16-19produced only the anchor-deprotected forms in high yield. However, inthe reactions of Comparative Example compounds 1 and 2, wherein 2 or 3hydroxyl groups substituted by long chain aliphatic hydrocarbon groupswere introduced into the anchor group, the yield of the deprotectedforms decreased (see Table 1 and Table 2). Therefrom it has beenconfirmed that the anchor compound of the present invention having onlyone hydroxyl group substituted by a long chain aliphatic hydrocarbongroup is a protecting reagent with broad utility, which permitsefficient progress of the removal reaction of the anchor in a high yieldeven when the reaction substrate contains a reactive functional groupsuch as a thiol group and the like.

TABLE 1 test compound yield(%) Example compound 16 94 Example compound17 97 Example compound 18 100 Comparative Example 23 compound 1Comparative Example 68 compound 2

TABLE 2 test compound yield(%) Example compound 16 100 Example compound17 98 Example compound 19 97 Comparative Example 84 compound 2

Experimental Example 2 Comparison of Anchor of the Present Invention andKnown Anchor in Yield of Deprotection Reaction of Anchor-Protected Formof Fmoc-Trp(Boc)-OH and Anchor-Protected form of Fmoc-Met-OH TestCompounds

The compounds described in the aforementioned Examples 20 and 21, andExamples 22 and 23, wherein Fmoc-Met-OH and Fmoc-Trp(Boc)-OH wereintroduced into the two kinds of anchors of the present invention,(hereinafter to be referred to as is Example compounds 20, 21, 22 and23) were used as test compounds.

In addition, Fmoc-Met-OBzl (3,4,5-tri-OC₁₈) and Fmoc-Trp(Boc)-OBzl(3,4,5-tri-OC₁₈) obtained by introducing Fmoc-Met-OH andFmoc-Trp(Boc)-OH, respectively, into the following formula:

which is the anchor molecule described in the aforementioned non-patentdocument 1 (hereinafter to be referred to as Bzl (3,4,5-tri-OC₁₈)OH),that is, the compounds described in the aforementioned ComparativeExamples 3 and 4 were used as test compounds (hereinafter to be referredto as Comparative Example compounds 3 and 4).

Experiment Method

(iii) To each test compound was added trifluoroacetic acid(TFA:H₂O:TIS=95:2.5:2.5) in triisopropylsilane-water at roomtemperature, and the mixture was stirred for 4 hr. The yield of theanchor-deprotected form, i.e., Fmoc-Met-OH, and that of the alkylatedform (the compound of the following formula A) were measured and theyields were calculated (Table 3).

(iv) To each test compound was added trifluoroacetic acid(TFA:H₂O:TIS=95:2.5:2.5) in triisopropylsilane-water at roomtemperature, and the mixture was stirred for 4 hr. The yield of theanchor-deprotected form, i.e., Fmoc-Trp-OH, and that of the alkylatedform (the compound of the following formula B) were measured, and theyields were calculated (Table 4).

Experimental Results

In both cases of the above-mentioned (iii) and (iv), the startingmaterial disappeared, and the deprotection reaction of Example compounds20-23 produced only the anchor-deprotected form (Fmoc-Met-OH orFmoc-Trp-OH) in high yield. However, in the reactions of ComparativeExample compounds 3 and 4, into which an anchor group wherein 3 hydroxylgroups were substituted by long chain aliphatic hydrocarbon groups wasintroduced, the yield of the anchor-deprotected form remarkablydecreased (see Table 3 and Table 4), and alkylated forms (A, B) whereina 3,4,5-tris(octadecyloxy)benzyl group derived from the anchor group wasintroduced into the methylthio group of Fmoc-Met-OH and the indolylgroup of Fmoc-Trp-OH, respectively, were by-produced in large amounts.

The chemical structure of each of the above-mentioned alkylated formswas confirmed by ¹H-NMR.

¹H-NMR (300 MHz, CDCl₃) for A: δ0.87(9H, t, J=6.9 Hz), 1.39-1.87(96H,m), 2.01-2.25(7H, m), 3.42-4.52(2H, m), 3.88-3.96(6H, m), 4.21-4.26(1H,m), 4.34-4.36(1H, m), 4.42-4.51(2H, m), 6.53(2H, dd, J=11.2 Hz, 3.1 Hz),7.27-7.43(4H, m), 7.60(2H, m), 7.78(2H, m);

¹H-NMR (300 MHz, CDCl₃) for B: δ0.86(9H, t, J=6.8 Hz), 1.20-1.77(96H,m), 3.29(2H, m), 3.79-3.90(8H, m), 4.20-4.23(1H, m), 4.27-4.51(3H, m),6.48(2H, m), 7.31-7.75(12H, m)

Therefrom it has been confirmed that the anchor compound of the presentinvention having only one hydroxyl group substituted by a long chainaliphatic hydrocarbon group can suppress side reactions such asalkylation (benzylation) derived from an anchor group and the like, andis a protecting reagent with broad utility, which permits efficientprogress of the removal reaction of the anchor in a high yield even whenthe reaction substrate contains a reactive functional group such as amethylthio group, an indolyl group and the like.

TABLE 3 test compound yield (%) alkylated form (%) Example compound 2087 N.D. Example compound 21 88 N.D. Comparative Example 29 65 compound 3N.D.: not detected

TABLE 4 test compound yield (%) alkylated form (%) Example compound 2278 N.D. Example compound 23 96 N.D. Comparative Example 26 68 compound 4N.D.: not detected

As mentioned above, when the aforementioned known protecting reagent(anchor), that is, a benzyl alcohol type anchor having two or three longchain alkoxy groups on the same benzene ring, is used, side reactionssuch as alkylation of amino acid residue by alkyl cation (benzyl cation)and the like derived from the anchor occur during removal of the anchorunder acidic conditions, and the yield of the anchor-deprotected productmarkedly decreases.

In view of these results, it is considered that the presence of plurallong chain alkoxy groups enhances electron-donatability on the benzenering, which in turn stabilizes benzyl cation species derived from adissociated anchor during removal of the anchor under acidic conditions,and the cation species promotes alkylation of nucleophilic groups suchas a thiol group of a cysteine residue, a methylthio group of amethionine residue, an indolyl group of a tryptophan residue and thelike in the reaction substrate. Thus, it has been clarified that peptidesynthesis including amino acid residues (e.g., Cys, Trp, His, Met etc.)capable of reacting with benzyl cation derived from the removed anchoris associated with a problem in that a high yield in the finaldeprotection and the like cannot be ensured when the aforementionedknown protecting reagents are used.

INDUSTRIAL APPLICABILITY

Using the particular benzylic compound of the present invention, auseful benzylic compound can be provided, which enables reactions to beperformed in a homogeneous liquid phase, can be used as a protectingreagent (anchor) permitting isolation and purification by filtration andwashing alone by changing the solvent composition after the reaction,and affords a resulting product in a high yield and at high purity whilesuppressing an alkylation reaction during deprotection even under acidicconditions. In addition, the present invention also provides a usefulpeptide synthesis reaction, and further, a useful organic synthesisreaction (including an oligonucleotide synthesis reaction) using theparticular benzylic compound of the present invention.

While some of the embodiments of the present invention have beendescribed in detail in the above, it will, however, be evident for thoseof ordinary skill in the art that various modifications and changes maybe made to the particular embodiments shown without substantiallydeparting from the novel teaching and advantages of the presentinvention. Such modifications and changes are encompassed in the spiritand scope of the present invention as set forth in the appended claims.

1. A benzylic compound represented by formula (I):

wherein Y is a hydroxyl group or an —NHR group; R is a hydrogen atom, an alkyl group or an aralkyl group; R^(a) is an organic group having an aliphatic hydrocarbon group, which has a total carbon number of not less than 14; each R^(b) is independently an alkoxy group having a carbon number of 1 to 6, a halogen atom, or an alkyl group having a carbon number of 1 to 6, which is optionally substituted by one or more halogen atoms; and n is an integer of 0-4.
 2. The benzylic compound according to claim 1, wherein the total carbon number of the organic group for R^(a) is 14-200.
 3. The benzylic compound according to claim 1, wherein the total carbon number of the organic group for R^(a) is 30-80.
 4. The benzylic compound according to claim 1, wherein n is an integer of 0-2, and each R^(b) is independently an alkoxy group having a carbon number of 1 to
 4. 5. The benzylic compound according to claim 1, wherein R^(a) is a group represented by formula (a):

wherein * indicates the position of a bond; m₁ is an integer of 1-10; each X₁ is independently a single bond, —O—, —S—, —COO—, —OCONH—, —NHCO— or —CONH—; R₁ and R₂ are each independently a divalent aliphatic hydrocarbon group having a carbon number of not less than 5; and R₃ is a hydrogen atom, or a group represented by formula (I′):

wherein * indicates the position of a bond; and other symbols are as defined in claim 1; a group represented by formula (b):

wherein * indicates indicates the position of a bond; m₂ is 1 or 2; n₁, n₂, n₃ and n₄ are each independently an integer of 0-2; each X₂, X₂′ in the number of m₂ and X₂″ are independently a single bond, —O—, —S—, —COO—, —OCONH—, —NHCO— or —CONH—; each R₄ and each R₆ are independently a hydrogen atom, a methyl group or an aliphatic hydrocarbon group having a carbon number of not less than 5; and R₅ is an aliphatic hydrocarbon group having a carbon number of not less than 5; a group represented by formula (c):

wherein * indicates the position of a bond; m₃ is an integer of 0-15; n₅ is an integer of 0-11; n₆ is an integer of 0-5; each X₃ is independently a single bond, —O—, —S—, —COO—, —OCONH—, —NHCO— or —CONH—; and each R₇ is independently a hydrogen atom, a methyl group or an aliphatic hydrocarbon group having a carbon number of not less than 5; or a group represented by formula (d):

wherein * indicates indicates the position of a bond; each X₄ is independently a single bond, —O—, —S—, —COO—, —OCONH—, —NHCO— or —CONH; R₆ is a divalent aliphatic hydrocarbon group; each R₉ is independently a monovalent aliphatic hydrocarbon group; n₇ is an integer of 1-5; and Ar is an arylene group.
 6. The benzylic compound according to claim 5, wherein R^(a) is a group represented by the formula (a) wherein m₁ is 1; X₁ is a single bond or —O—; R₁ and R₂ are each independently a divalent aliphatic hydrocarbon group having a carbon number of 5-80; and R₃ is a hydrogen atom, or a group represented by formula (I″):

wherein * indicates the position of a bond; and Y is as defined in claim 1, or formula (I″′):

wherein * indicates the position of a bond; and Y is as defined in claim 1; a group represented by formula (b) wherein m₂ is 1; n₁, n₂, n₃ and n₄ are each independently 0 or 1; X₂, X₂′ and X₂″ are each independently a single bond, or —O—; R₄ and R₆ are each independently a hydrogen atom, a methyl group or an aliphatic hydrocarbon group having a carbon number of 5 to 80; and R₅ is an aliphatic hydrocarbon group having a carbon number of 5 to 80; a group represented by formula (c) wherein m₃ is an integer of 1-5; n₅ is an integer of 0-2; n₆ is an integer of 0-3; X₃ in the number of m₃ is —O—; and each R₇ is independently an aliphatic hydrocarbon group having a carbon number of 5 to 80; or a group represented by formula (d) wherein each X₄ is —O—; each R₈ and R₉ are independently a monovalent or divalent aliphatic hydrocarbon group having a carbon number of 5 to 80; n ₇ is an integer of 1-3; and Ar is phenylene.
 7. The benzylic compound according to claim 5, wherein R^(a) is a group represented by formula (a) wherein m₁ is 1; X₁ is —O—; R₁ and R₂ are each independently an alkylene group having a carbon number of 8 to 60; and R₃ is a hydrogen atom; a group represented by formula (b) wherein m₂ is 1; n₁, n₂, n₃ and n₄ are each 1; X₂, X₂′ and X₂″ are each —O—; and R₄, R₅ and R₆ are each independently an alkyl group having a carbon number of 8 to 60; a group represented by formula (c) wherein m₃ is 2 or 3; n ₅ is 1; n₆ is 2 or 3; X₃ in the number of m₃ is —O—; and each R₇ is independently an alkyl group having a carbon number of 8 to 60; or a group represented by formula (d) wherein X₄ in the number of n₇ is —O—; R₈ is an alkylene group having a carbon number of 1 to 3; R₉ in the number of n₇ is each independently an alkyl group having a carbon number of 8 to 60; n₇ is an integer of 1-3; and Ar is phenylene.
 8. The benzylic compound according to claim 5, wherein R^(a) is a group represented by formula (a) wherein m₁ is 1; X₁ is —O—; R₁ and R₂ are each independently an alkylene group having a carbon number of 14 to 30; and R₃ is a hydrogen atom; a group represented by formula (b) wherein m₂ is 1; n₁, n₂, n₃ and n₄ are each 1; X₂, X₂′ and X₂″ are each —O—; and R₄, R₅ and R₆ are each independently an alkyl group having a carbon number of 14 to 30; a group represented by formula (c) wherein m₃ is 2 or 3; n₅ is 1; n₆ is 3; X₃ in the number of m₃ is —O—; and R₇ in the number of m₃ is each independently an alkyl group having a carbon number of 14 to 30; or a group represented by formula (d) wherein X₄ in the number of n₇ is —O—; R₈ is an alkylene group having a carbon number of 1 to 3; R₉ in the number of n₇ is each independently an alkyl group having a carbon number of 14 to 30; n ₇ is 2 or 3; and Ar is phenylene.
 9. The benzylic compound according to claim 1, wherein OR^(a) is present at the 2-position or the 4-position on the benzene ring.
 10. The benzylic compound according to claim 1, wherein R^(b) is a methoxy group.
 11. The benzylic compound according to claim 1, wherein Y is a hydroxyl group.
 12. The benzylic compound according to claim 1, wherein Y is an —NHR group wherein R is as defined in claim
 1. 13. The benzylic compound according to claim 11, which is selected from the group consisting of 4-(12′-docosyloxy-1′-dodecyloxy)benzyl alcohol, 4-(12′-docosyloxy-1′-dodecyloxy)-2-methoxybenzyl alcohol, 4-(12′-docosyloxy-1′-dodecyloxy)-2-methoxybenzylamine, 2-(12′-docosyloxy-1′-dodecyloxy)-4-methoxybenzyl alcohol, 2-(12′-docosyloxy-1′-dodecyloxy)-4-methoxybenzylamine, 4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)benzyloxy]benzyl alcohol, 2-[3′,5′-di(docosyloxy)benzyloxy]-4-methoxybenzyl alcohol, 2-methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzyl alcohol, 2-methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzylamine, 4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzyl alcohol, 4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzyl alcohol, 1,22-bis[12-(4-hydroxymethyl-3-methoxyphenoxy)dodecyloxy]docosane, and 1,22-bis[12-(2-hydroxymethyl-5-methoxyphenoxy)dodecyloxy]docosane.
 14. The benzylic compound according to claim 11, which is selected from the group consisting of 2-docosyloxy-4-methoxybenzyl alcohol, 2-methoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzyl alcohol, 3,5-dimethoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzyl alcohol, N-(4-hydroxymethyl-3-methoxyphenyl) 3,4,5-tris(octadecyloxy)cyclohexylcarboxamide, N-(5-hydroxymethyl-2-methoxyphenyl) 3,4,5-tris(octadecyloxy)cyclohexylcarboxamide, and N-(4-hydroxymethylphenyl) 3,4,5-tris(octadecyloxy)cyclohexylcarboxamide.
 15. A reagent for protecting a carboxyl group of amino acid or peptide, comprising the benzylic compound according to claim
 11. 16. A reagent for protecting the C-terminal of amino acid or peptide, comprising the benzylic compound according to claim
 11. 17. A method of producing a peptide by a liquid phase synthesis process, comprising: (1) bonding the benzylic compound according to claim 1 to amino acid or peptide, and (2) precipitating the bonded product of the benzylic compound with amino acid or peptide from (1).
 18. A method of producing a peptide by a liquid phase synthesis process, comprising: (1) obtaining a C-protected amino acid or C-protected peptide, comprising condensing the benzylic compound according to claim 1 with a C-terminal of N-protected amino acid or N-protected peptide, (2) removing the protecting group of the N-terminal of the amino acid or peptide from (1), (3) condensing the N-terminal of the amino acid or peptide from (2) with a N-protected amino acid or N-protected peptide to produce a peptide, and (4) precipitating the peptide from (3).
 19. The method according to claim 18, further comprising one or more repeats of the following (5)-(7) (5) deprotecting the N-terminal of the peptide from (4), (6) condensing the N-terminal of peptide from (5) with N-protected amino acid or N-protected peptide, and (7) precipitating the peptide from (6).
 20. The method according to claim 18, further comprising, after the precipitation (7), removing the protecting group of the C-terminal of the peptide.
 21. In a method of producing a peptide compound, the improvement comprising protecting a functional group of the peptide with the benzylic compound of claim
 1. 22. In a method of producing an organic compound, the improvement comprising protecting a functional group with the benzylic compound of claim
 1. 23. A benzylic compound adduct protected by the benzylic compound according to claim
 1. 24. A compound represented by formula (III):

wherein m₃′ is 1-3; each R₇′ is independently an alkylene group having a carbon number of 14 to 30, and Z′ is a hydroxyl group or a leaving group.
 25. The compound according to claim 24, wherein, in the formula (III), m₃′ is 3, and Z′ is a hydroxyl group, a halogen atom, an alkylsulfonyloxy group optionally substituted by one or more halogen atoms, or an optionally substituted arylsulfonyloxy group. 